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  • 1.
    Agarwal, Prasoon
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Collier, Paul
    Fritz, Markus Hsi-Yang
    Benes, Vladimir
    Wiklund, Helena Jernberg
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Singh, Umashankar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    CGGBP1 mitigates cytosine methylation at repetitive DNA sequences2015Inngår i: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, artikkel-id 390Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: CGGBP1 is a repetitive DNA-binding transcription regulator with target sites at CpG-rich sequences such as CGG repeats and Alu-SINEs and L1-LINEs. The role of CGGBP1 as a possible mediator of CpG methylation however remains unknown. At CpG-rich sequences cytosine methylation is a major mechanism of transcriptional repression. Concordantly, gene-rich regions typically carry lower levels of CpG methylation than the repetitive elements. It is well known that at interspersed repeats Alu-SINEs and L1-LINEs high levels of CpG methylation constitute a transcriptional silencing and retrotransposon inactivating mechanism. Results: Here, we have studied genome-wide CpG methylation with or without CGGBP1-depletion. By high throughput sequencing of bisulfite-treated genomic DNA we have identified CGGBP1 to be a negative regulator of CpG methylation at repetitive DNA sequences. In addition, we have studied CpG methylation alterations on Alu and L1 retrotransposons in CGGBP1-depleted cells using a novel bisulfite-treatment and high throughput sequencing approach. Conclusions: The results clearly show that CGGBP1 is a possible bidirectional regulator of CpG methylation at Alus, and acts as a repressor of methylation at L1 retrotransposons.

  • 2.
    Allen, Marie
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bjerke, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Lab Med, SE-14186 Stockholm, Sweden..
    Edlund, Hanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Teknisk-naturvetenskapliga vetenskapsområdet, Biologiska sektionen, Institutionen för organismbiologi, Evolution och utvecklingsbiologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Origin of the U87MG glioma cell line: Good news and bad news2016Inngår i: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, nr 354, artikkel-id 354re3Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human tumor-derived cell lines are indispensable tools for basic and translational oncology. They have an infinite life span and are easy to handle and scalable, and results can be obtained with high reproducibility. However, a tumor-derived cell line may not be authentic to the tumor of origin. Two major questions emerge: Have the identity of the donor and the actual tumor origin of the cell line been accurately determined? To what extent does the cell line reflect the phenotype of the tumor type of origin? The importance of these questions is greatest in translational research. We have examined these questions using genetic profiling and transcriptome analysis in human glioma cell lines. We find that the DNA profile of the widely used glioma cell line U87MG is different from that of the original cells and that it is likely to be a bona fide human glioblastoma cell line of unknown origin.

  • 3.
    Almstedt, Elin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Elgendy, Ramy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Hekmati, Neda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Rosén, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Wärn, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Olsen, Thale Kristin
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden..
    Dyberg, Cecilia
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden..
    Doroszko, Milena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Larsson, Ida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Sundström, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Arsenian Henriksson, Marie
    Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
    Påhlman, Sven
    Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden..
    Bexell, Daniel
    Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Lund, Sweden..
    Vanlandewijck, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi. Department of Medicine, Integrated Cardio-Metabolic Centre Single Cell Facility, Karolinska Institutet, Stockholm, Sweden..
    Kogner, Per
    Childhood Cancer Research Unit, Department of Women's and Children's Health, Karolinska Institutet, Stockholm, Sweden.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden..
    Krona, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Integrative discovery of treatments for high-risk neuroblastoma.2020Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 11, nr 1, artikkel-id 71Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Despite advances in the molecular exploration of paediatric cancers, approximately 50% of children with high-risk neuroblastoma lack effective treatment. To identify therapeutic options for this group of high-risk patients, we combine predictive data mining with experimental evaluation in patient-derived xenograft cells. Our proposed algorithm, TargetTranslator, integrates data from tumour biobanks, pharmacological databases, and cellular networks to predict how targeted interventions affect mRNA signatures associated with high patient risk or disease processes. We find more than 80 targets to be associated with neuroblastoma risk and differentiation signatures. Selected targets are evaluated in cell lines derived from high-risk patients to demonstrate reversal of risk signatures and malignant phenotypes. Using neuroblastoma xenograft models, we establish CNR2 and MAPK8 as promising candidates for the treatment of high-risk neuroblastoma. We expect that our method, available as a public tool (targettranslator.org), will enhance and expedite the discovery of risk-associated targets for paediatric and adult cancers.

  • 4.
    Almstedt, Elin
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala University.
    Rosén, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Hekmati, Neda
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Gloger, Marleen
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Koltowska, Kaska
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Krona, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Real-time evaluation of glioblastoma treatmentsin patient-specic zebrash xenograftsManuskript (preprint) (Annet vitenskapelig)
  • 5.
    Arvidsson, Per I.
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Drug Discovery & Development Platform & Division of Translational Medicine and Chemical Biology, Department of Medical Biochemistry and Biophysics, Karolinska Institutet, Stockholm, Sweden.
    Sandberg, Kristian
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Farmaceutiska fakulteten, Institutionen för läkemedelskemi, Avdelningen för organisk farmaceutisk kemi. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Forsberg-Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Open for collaboration: an academic platform for drug discovery and development at SciLifeLab2016Inngår i: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 21, nr 10, s. 1690-1698Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    The Science for Life Laboratory Drug Discovery and Development (SciLifeLab DDD) platform reaches out to Swedish academia with an industry-standard infrastructure for academic drug discovery, supported by earmarked funds from the Swedish government. In this review, we describe the build-up and operation of the platform, and reflect on our first two years of operation, with the ambition to share learnings and best practice with academic drug discovery centers globally. We also discuss how the Swedish Teacher Exemption Law, an internationally unique aspect of the innovation system, has shaped the operation. Furthermore, we address how this investment in infrastructure and expertise can be utilized to facilitate international collaboration between academia and industry in the best interest of those ultimately benefiting the most from translational pharmaceutical research - the patients.

  • 6. Attarha, Sanaz
    et al.
    Roy, Ananya
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden..
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Tchougounova, Elena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Mast cells modulate proliferation, migration and sternness of glioma cells through downregulation of GSK3 beta expression and inhibition of STAT3 activation2017Inngår i: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 37, s. 81-92Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glioblastoma (GBM) heterogeneity is the main obstacle to efficient treatment due to the existence of sub population of cells with increased tumorigenicity and network of tumor associated parenchymal cells in the tumor microenvironment. We previously demonstrated that mast cells (MCs) infiltrate mouse and human gliomas in response to variety of signals in a glioma grade-dependent manner. However, the role of MCs in glioma development and the mechanisms behind MCs-glioma cells interaction remain unidentified. In the present study, we show that MCs upon activation by glioma cells produce soluble factors including IL-6, which are documented to be involved in cancer-related activities. We observe 'tumor educated' MCs decrease glioma cell proliferation and migration, reduce self-renewal capacity and expression of stemness markers but in turn promote glioma cell differentiation. 'Tumor educated' MC derived mediators exert these effects via inactivation of STAT3 signaling pathway through GSK3 beta down-regulation. We identified 'tumor educated' MC derived IL-6 as one of the contributors among the complex mixture of MCs mediators, to be partially involved in the observed MC induced biological effect on glioma cells. Thus, MC mediated abolition of STAT3 signaling hampers glioma cell proliferation and migration by suppressing their stemness and inducing differentiation via down-regulation of GSK3 beta expression. Targeting newly identified inflammatory MC-STAT3 axis could contribute to patient tailored therapy and unveil potential future therapeutic opportunities for patients.

  • 7.
    Babateen, Omar M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Jin, Zhe
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Bhandage, Amol K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Korol, Sergiy V.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Fysiologi.
    Westermark, Bengt
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Nilsson, Karin Forsberg
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Uhrbom, Lene
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Smits, Anja
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    Birnir, Bryndis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurologi.
    GABA-A receptor currents in a cell line (U3047MG) derived from a human glioblastoma tumor are enhanced by etomidate, propofol and diazepam2014Inngår i: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, nr S696, s. 100-100, artikkel-id P74Artikkel i tidsskrift (Annet vitenskapelig)
  • 8.
    Barash, Uri
    et al.
    Rappaport Fac Med, TICC, Haifa, Israel.
    Spyrou, Argyris
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Liu, Pei
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Vlodaysky, Euvgeni
    Rambam Hlth Care Campus, Dept Pathol, Haifa, Israel.
    Zhu, Chenchen
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Luo, Juanjuan
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Su, Dongsheng
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Ilhan, Neta
    Rappaport Fac Med, TICC, Haifa, Israel.
    Forsberg Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Vlodaysky, Israel
    Rappaport Fac Med, TICC, Haifa, Israel.
    Yang, Xiaojun
    Shantou Univ, Med Coll, Shantou, Peoples R China.
    Heparanase promotes glioma progression via enhancing CD24 expression2019Inngår i: International Journal of Cancer, ISSN 0020-7136, E-ISSN 1097-0215, Vol. 145, nr 6, s. 1596-1608Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Heparanase is an endo-beta-d-glucuronidase that cleaves heparan sulfate (HS) side chains of heparan sulfate proteoglycans. Compelling evidence tie heparanase levels with all steps of tumor formation including tumor initiation, growth, metastasis and chemo-resistance, likely involving augmentation of signaling pathways and gene transcription. In order to reveal the molecular mechanism(s) underlying the protumorigenic properties of heparanase, we established an inducible (Tet-on) system in U87 human glioma cells and applied gene array methodology in order to identify genes associated with heparanase induction. We found that CD24, a mucin-like cell adhesion protein, is consistently upregulated by heparanase and by heparanase splice variant devoid of enzymatic activity, whereas heparanase gene silencing was associated with decreased CD24 expression. This finding was further substantiated by a similar pattern of heparanase and CD24 immunostaining in glioma patients (Pearson's correlation; R = 0.66, p = 0.00001). Noteworthy, overexpression of CD24 stimulated glioma cell migration, invasion, colony formation in soft agar and tumor growth in mice suggesting that CD24 functions promote tumor growth. Likewise, anti-CD24 neutralizing monoclonal antibody attenuated glioma tumor growth, and a similar inhibition was observed in mice treated with a neutralizing mAb directed against L1 cell adhesion molecule (L1CAM), a ligand for CD24. Importantly, significant shorter patient survival was found in heparanase-high/CD24-high tumors vs. heparanase-high/CD24-low tumors for both high-grade and low-grade glioma (p = 0.02). Our results thus uncover a novel heparanase-CD24-L1CAM axis that plays a significant role in glioma tumorigenesis.

  • 9.
    Baskaran, Sathish
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Almstedt, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Hansson, Caroline
    Sahlgrenska Cancer Center, Institute of Medicine, Gothenburg, Sweden.
    Kalushkova, Antonia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Atienza Párraga, Alba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Spyrou, Argyris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Forsberg Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Jernberg Wiklund, Helena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Elfineh, Lioudmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Weishaupt, Holger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Kundu, Soumi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Krona, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    ZBTB16 orchestrates growth and invasion in glioblastomaManuskript (preprint) (Annet vitenskapelig)
  • 10.
    Baskaran, Sathishkumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Department of IGP, Uppsala University.
    New Molecular Approaches to Glioblastoma Therapy2017Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Glioblastoma (GBM) is the most common high-grade brain tumor diagnosed in patients who are more than 50 years of age. The standard of care treatment is surgery, followed by radiotherapy and chemotherapy. The median life expectancy of patients is only between 12 to 15 months after receiving current treatment regimes. Hence, identification of new therapeutic compounds and gene targets are highly warranted. This thesis describes four interlinked studies to attain this goal. In study 1, we explored drug combination effects in a material of 41 patient-derived GBM cell (GC) cultures. Synergies between three compounds, pterostilbene, gefitinib, and sertraline, resulted in effective killing of GC and can be predicted by biomarkers. In study 2, we performed a large-scale screening of FDA approved compounds (n=1544) in a larger panel of GCs (n=106). By combining the large-scale drug response data with GCs genomics data, we built a novel computational model to predict the sensitivity of each compound for a given GC. A notable finding was that GCs respond very differently to proteasome inhibitors in both in-vitro and in-vivo. In study 3, we explored new gene targets by RNAi (n=1112) in a panel of GC cells. We found that loss of transcription factor ZBTB16/PLZF inhibits GC cell viability, proliferation, migration, and invasion. These effects were due to downregulation of c-MYC and Cyclin B1 after the treatment. In study 4, we tested the genomic stability of three GCs upon multiple passaging. Using molecular and mathematical analyses, we showed that the GCs undergo both systematic adaptations and sequential clonal takeovers. Such changes tend to affect a broad spectrum of pathways. Therefore, a systematic analysis of cell culture stability will be essential to make use of primary cells for translational oncology.

    Taken together, these studies deepen our knowledge of the weak points of GBM and provide several targets and biomarkers for further investigation. The work in this thesis can potentially facilitate the development of targeted therapies and result in more accurate tools for patient diagnostics and stratification. 

    Delarbeid
    1. Case-specific potentiation of glioblastoma drugs by pterostilbene
    Åpne denne publikasjonen i ny fane eller vindu >>Case-specific potentiation of glioblastoma drugs by pterostilbene
    Vise andre…
    2016 (engelsk)Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, nr 45, s. 73200-73215Artikkel i tidsskrift (Fagfellevurdert) Published
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-309806 (URN)10.18632/oncotarget.12298 (DOI)000387452100060 ()
    Forskningsfinansiär
    Swedish Research CouncilSwedish Cancer SocietySwedish Childhood Cancer Foundation
    Tilgjengelig fra: 2016-09-28 Laget: 2016-12-07 Sist oppdatert: 2019-01-22bibliografisk kontrollert
    2. Targeting tumor heterogeneity: multi-omic modeling of glioblastoma drug response using an open-access library of patient-derived cells
    Åpne denne publikasjonen i ny fane eller vindu >>Targeting tumor heterogeneity: multi-omic modeling of glioblastoma drug response using an open-access library of patient-derived cells
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    GBM, Proteasome inhibitors, Precision medicine, Bortezomib, drug predictions
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot molekylärbiologi; Onkologi; Bioinformatik; Medicinsk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-329756 (URN)
    Tilgjengelig fra: 2017-09-20 Laget: 2017-09-20 Sist oppdatert: 2018-01-13
    3. Loss of transcription factor ZBTB16 induces cell death in patient-derived GBM cell lines
    Åpne denne publikasjonen i ny fane eller vindu >>Loss of transcription factor ZBTB16 induces cell death in patient-derived GBM cell lines
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    PLZF, ZBTB16, GBM, Glioblastoma
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot molekylär cellbiologi; Onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-329752 (URN)
    Tilgjengelig fra: 2017-09-20 Laget: 2017-09-20 Sist oppdatert: 2018-01-13
    4. Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages: glioblastoma cells for precision medicine
    Åpne denne publikasjonen i ny fane eller vindu >>Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages: glioblastoma cells for precision medicine
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    Patient derived GBM cell cultures, Systems biology, Subclones, Glioma stem cell cultures, GBM subtype
    HSV kategori
    Forskningsprogram
    Onkologi; Biologi; Medicinsk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-329742 (URN)
    Tilgjengelig fra: 2017-09-20 Laget: 2017-09-20 Sist oppdatert: 2017-10-22
  • 11.
    Baskaran, Sathishkumar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Department of IGP, Uppsala University.
    Johansson, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Hansson, Caroline
    Sahlgrenska Cancer Center, University of Gothenburg.
    Spyrou, Argyris
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Kalushkova, Antonia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Ramachandran, Mohanraj
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Atienza Párraga, Alba
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nordling, Torbjörn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Elfineh, Lioudmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Martens, Ulf
    Cell screening facility, Science for Life Laboratory Stockholm.
    Häggblad, Maria
    Cell screening facility, Science for Life Laboratory Stockholm.
    Kundu, Soumi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Forsberg Nilsson, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Lundgren, Bo
    Cell screening facility, Science for Life Laboratory Stockholm.
    Krona, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Loss of transcription factor ZBTB16 induces cell death in patient-derived GBM cell linesManuskript (preprint) (Annet vitenskapelig)
  • 12.
    Baskaran, Sathishkumar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Mayrhofer, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Göransson Kultima, Hanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Bergström, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Elfineh, Lioudmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk genetik och genomik.
    Isaksson, Anders
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages2018Inngår i: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, nr 8, s. 1080-1091Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Primary glioblastoma cell (GC) cultures have emerged as a key model in brain tumor research, with the potential to uncover patient-specific differences in therapy response. However, there is limited quantitative information about the stability of such cells during the initial 20-30 passages of culture.

    Methods: We interrogated 3 patient-derived GC cultures at dense time intervals during the first 30 passages of culture. Combining state-of-the-art signal processing methods with a mathematical model of growth, we estimated clonal composition, rates of change, affected pathways, and correlations between altered gene dosage and transcription.

    Results: We demonstrate that GC cultures undergo sequential clonal takeovers, observed through variable proportions of specific subchromosomal lesions, variations in aneuploid cell content, and variations in subpopulation cell cycling times. The GC cultures also show significant transcriptional drift in several metabolic and signaling pathways, including ribosomal synthesis, telomere packaging and signaling via the mammalian target of rapamycin, Wnt, and interferon pathways, to a high degree explained by changes in gene dosage. In addition to these adaptations, the cultured GCs showed signs of shifting transcriptional subtype. Compared with chromosomal aberrations and gene expression, DNA methylations remained comparatively stable during passaging, and may be favorable as a biomarker.

    Conclusion: Taken together, GC cultures undergo significant genomic and transcriptional changes that need to be considered in functional experiments and biomarker studies that involve primary glioblastoma cells.

  • 13.
    Baskaran, Sathishkumar
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Department of IGP, Uppsala University.
    Mayrhofer, Markus
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Kultima, Hanna
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Elfineh, Lioudmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Cavelier, Lucia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Isaksson, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages: glioblastoma cells for precision medicineManuskript (preprint) (Annet vitenskapelig)
  • 14.
    Bolin, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies2016Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Medulloblastomas are the most frequent malignant childhood brain tumors, arising in the posterior fossa of children. The overall 5-year survival is 70%, although children often suffer severe long-term side effects from standard medical care. To improve progression-free survival and quality of life for these children, finding new therapeutic targets in medulloblastoma is imperative.

    Medulloblastoma is divided in to four molecular subgroups (WNT, SHH, Group 3 and Group 4) based on key developmental pathways essential for the initiation and maintenance of tumor development. The MYC family of proto-oncogenes regulates cell proliferation and differentiation in normal brain. Aberrant expression of MYC proteins occurs commonly in medulloblastoma.

    Our studies on Group 3 medulloblastoma identify the transcription factor SOX9 as a novel target for the E3 ubiquitin ligase FBW7, and show that increased stability of SOX9 confers an increased metastatic potential in medulloblastoma. Moreover, SOX9-positive cells drive distant recurrences in medulloblastoma when combining two regulatable TetON/OFF systems. MYCN depletion leads to increased SOX9 expression in Group 3 medulloblastoma cells, and the recurring tumor cells are more migratory in vitro and in vivo. Segueing to treatment of medulloblastoma, we show that BET bromodomain inhibition specifically targets MYC-amplified medulloblastoma cells by downregulating MYC and MYC-transcriptional targets, and that combining BET bromodomain- and cyclin-dependent kinase- inhibition improves survival in mice compared to single therapy. Combination treatment results in decreased MYC levels and increased apoptosis, and RNA-seq confirms upregulation of apoptotic markers along with downregulated MYC target genes in medulloblastoma cells.

    This thesis addresses novel findings in transcription factor biology, recurrence and treatment in Group 3 medulloblastoma, the most malignant subgroup of the disease.

    Delarbeid
    1. FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
    Åpne denne publikasjonen i ny fane eller vindu >>FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
    Vise andre…
    2016 (engelsk)Inngår i: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 35, nr 20, s. 2192-2212Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    SOX9 is a master transcription factor that regulates development and stem cell programs. However, its potential oncogenic activity and regulatory mechanisms that control SOX9 protein stability are poorly understood. Here, we show that SOX9 is a substrate of FBW7, a tumor suppressor, and a SCF (SKP1/CUL1/F-box)-type ubiquitin ligase. FBW7 recognizes a conserved degron surrounding threonine 236 (T236) in SOX9 that is phosphorylated by GSK3 kinase and consequently degraded by SCFFBW7 alpha. Failure to degrade SOX9 promotes migration, metastasis, and treatment resistance in medulloblastoma, one of the most common childhood brain tumors. FBW7 is either mutated or downregulated in medulloblastoma, and in cases where FBW7 mRNA levels are low, SOX9 protein is significantly elevated and this phenotype is associated with metastasis at diagnosis and poor patient outcome. Transcriptional profiling of medulloblastoma cells expressing a degradation-resistant SOX9 mutant reveals activation of pro-metastatic genes and genes linked to cisplatin resistance. Finally, we show that pharmacological inhibition of PI3K/AKT/mTOR pathway activity destabilizes SOX9 in a GSK3/FBW7-dependent manner, rendering medulloblastoma cells sensitive to cytostatic treatment.

    Emneord
    FBW7, SOX9, Medulloblastoma, FBXW7, ubiquitin, migration, metastasis, drug resistance
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-274626 (URN)10.15252/embj.201693889 (DOI)000385708000004 ()
    Forskningsfinansiär
    Swedish Childhood Cancer FoundationSwedish Cancer SocietySwedish Research CouncilEU, European Research Council, 640275Ragnar Söderbergs stiftelseSwedish Society of MedicineÅke Wiberg FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceThe Karolinska Institutet's Research Foundation
    Merknad

    Aldwin Suryo Rahmanto and Vasil Savov contributed equally to this work as first authors

    Andrä Brunner, Sara Bolin and Holger Weishaupt contributed equally to this work as second authors

    Fredrik J Swartling and Olle Sangfelt contributed equally to this work as corresponding authors

    Tilgjengelig fra: 2016-01-24 Laget: 2016-01-24 Sist oppdatert: 2018-01-10bibliografisk kontrollert
    2. Metastasis and tumor recurrence from rare SOX9-positive cells in MYCN-driven medulloblastoma
    Åpne denne publikasjonen i ny fane eller vindu >>Metastasis and tumor recurrence from rare SOX9-positive cells in MYCN-driven medulloblastoma
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    SOX9, medulloblastoma, relapse, recurrence, MYCN, mouse model, pediatric cancer
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-274629 (URN)
    Tilgjengelig fra: 2016-01-24 Laget: 2016-01-24 Sist oppdatert: 2018-01-10
    3. BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
    Åpne denne publikasjonen i ny fane eller vindu >>BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
    Vise andre…
    2014 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, nr 4, s. 912-925Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Purpose:

    MYC-amplified medulloblastomas are highly lethal tumors. Bromodomain and extraterminal (BET) bromodomain inhibition has recently been shown to suppress MYC-associated transcriptional activity in other cancers. The compound JQ1 inhibits BET bromodomain-containing proteins, including BRD4. Here, we investigate BET bromodomain targeting for the treatment of MYC-amplified medulloblastoma.

    Experimental Design:

    We evaluated the effects of genetic and pharmacologic inhibition of BET bromodomains on proliferation, cell cycle, and apoptosis in established and newly generated patient- and genetically engineered mouse model (GEMM)-derived medulloblastoma cell lines and xenografts that harbored amplifications of MYC or MYCN. We also assessed the effect of JQ1 on MYC expression and global MYC-associated transcriptional activity. We assessed the in vivo efficacy of JQ1 in orthotopic xenografts established in immunocompromised mice.

    Results:

    Treatment of MYC-amplified medulloblastoma cells with JQ1 decreased cell viability associated with arrest at G1 and apoptosis. We observed downregulation of MYC expression and confirmed the inhibition of MYC-associated transcriptional targets. The exogenous expression of MYC from a retroviral promoter reduced the effect of JQ1 on cell viability, suggesting that attenuated levels of MYC contribute to the functional effects of JQ1. JQ1 significantly prolonged the survival of orthotopic xenograft models of MYC-amplified medulloblastoma (P < 0.001). Xenografts harvested from mice after five doses of JQ1 had reduced the expression of MYC mRNA and a reduced proliferative index.

    Conclusion:

    JQ1 suppresses MYC expression and MYC-associated transcriptional activity in medulloblastomas, resulting in an overall decrease in medulloblastoma cell viability. These preclinical findings highlight the promise of BET bromodomain inhibitors as novel agents for MYC-amplified medulloblastoma.

    Emneord
    medulloblastoma, MYC
    HSV kategori
    Forskningsprogram
    Onkologi
    Identifikatorer
    urn:nbn:se:uu:diva-217950 (URN)10.1158/1078-0432.CCR-13-2281 (DOI)000331875500015 ()
    Tilgjengelig fra: 2014-02-06 Laget: 2014-02-06 Sist oppdatert: 2017-12-06bibliografisk kontrollert
    4. Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
    Åpne denne publikasjonen i ny fane eller vindu >>Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
    Vise andre…
    (engelsk)Artikkel i tidsskrift (Annet vitenskapelig) Submitted
    Emneord
    MYC, BET Bromodomains, Cyclin dependent kinases, Treatment, Medulloblastoma
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-300906 (URN)
    Tilgjengelig fra: 2016-08-15 Laget: 2016-08-15 Sist oppdatert: 2016-10-11
  • 15.
    Bolin, Sara
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Borgenvik, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Persson, Camilla U
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Sundström, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Qi, Jun
    Bradner, James E
    Cho, Yoon-Jae
    Weishaupt, Holger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Swartling, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastomaArtikkel i tidsskrift (Annet vitenskapelig)
  • 16.
    Bolin, Sara M.
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Lau, Jasmine
    Chen, Justin
    Savov, Vasil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Persson, Anders I.
    Hede, Sanna-Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Weiss, William A.
    Swartling, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Glial origin for MYCN-driven medulloblastoma and targeted prosenescence therapies2014Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, nr 19Artikkel i tidsskrift (Annet vitenskapelig)
  • 17.
    Caja, Laia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Tzavlaki, Kalliopi
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Dadras, Mahsa Shahidi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Tan, E-Jean
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Hatem, Gad
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Maturi, Naga Prathyusha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Morén, Anita
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Wik, Lotta
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Watanabe, Yukihide
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Univ Tsukuba, Dept Expt Pathol, Fac Med, Tsukuba, Ibaraki, Japan.
    Savary, Katia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Univ Reims, UMR CNRS MEDyC 7369, Reims, France.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Heldin, Carl-Henrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwiginstitutet för cancerforskning.
    Moustakas, Aristidis
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells2018Inngår i: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, nr 19, s. 2515-2531Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glioblastoma multiforme is a brain malignancy characterized by high heterogeneity, invasiveness, and resistance to current therapies, attributes related to the occurrence of glioma stem cells (GSCs). Transforming growth factor beta (TGF beta) promotes self-renewal and bone morphogenetic protein (BMP) induces differentiation of GSCs. BMP7 induces the transcription factor Snail to promote astrocytic differentiation in GSCs and suppress tumor growth in vivo. We demonstrate that Snail represses stemness in GSCs. Snail interacts with SMAD signaling mediators, generates a positive feedback loop of BMP signaling and transcriptionally represses the TGFB1 gene, decreasing TGF beta 1 signaling activity. Exogenous TGF beta 1 counteracts Snail function in vitro, and in vivo promotes proliferation and re-expression of Nestin, confirming the importance of TGFB1 gene repression by Snail. In conclusion, novel insight highlights mechanisms whereby Snail differentially regulates the activity of the opposing BMP and TGF beta pathways, thus promoting an astrocytic fate switch and repressing stemness in GSCs.

  • 18.
    Cancer, Matko
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Drews, Lisa F.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bengtsson, Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bolin, Sara
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Rosén, Gabriela
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Westermark, Bengt
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Nelander, Sven
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Forsberg Nilsson, Karin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Uhrbom, Lene
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Weishaupt, Holger
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Johansson, Fredrik K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    BET and Aurora Kinase A inhibitors synergize against MYCN-positive human glioblastoma cells2019Inngår i: Cell Death and Disease, ISSN 2041-4889, E-ISSN 2041-4889, Vol. 10, artikkel-id 881Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glioblastoma multiforme (GBM) is the most common primary malignant brain tumor in adults. Patients usually undergo surgery followed by aggressive radio- and chemotherapy with the alkylating agent temozolomide (TMZ). Still, median survival is only 12-15 months after diagnosis. Many human cancers including GBMs demonstrate addiction to MYC transcription factor signaling and can become susceptible to inhibition of MYC downstream genes. JQ1 is an effective inhibitor of BET Bromodomains, a class of epigenetic readers regulating expression of downstream MYC targets. Here, we show that BET inhibition decreases viability of patient-derived GBM cell lines. We propose a distinct expression signature of MYCN-elevated GBM cells that correlates with significant sensitivity to BET inhibition. In tumors showing JQ1 sensitivity, we found enrichment of pathways regulating cell cycle, DNA damage response and repair. As DNA repair leads to acquired chemoresistance to TMZ, JQ1 treatment in combination with TMZ synergistically inhibited proliferation of MYCN-elevated cells. Bioinformatic analyses further showed that the expression of MYCN correlates with Aurora Kinase A levels and Aurora Kinase inhibitors indeed showed synergistic efficacy in combination with BET inhibition. Collectively, our data suggest that BET inhibitors could potentiate the efficacy of either TMZ or Aurora Kinase inhibitors in GBM treatment.

  • 19.
    Cane, Gaëlle
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Leuchowius, Karl-Johan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Söderberg, Ola
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Kamali-Moghaddam, Masood
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Jarvis, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Helbring, Irene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Pardell, Katerina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Ebai, Tonge
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Koos, Björn
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Protein Diagnostics by Proximity Ligation: Combining Multiple Recognition and DNA Amplification for Improved Protein Analyses2017Inngår i: Molecular Diagnostics (Third Edition), 2016: Academia Press, 2017, 3, s. 219-231Kapittel i bok, del av antologi (Fagfellevurdert)
    Abstract [en]

    Proximity ligation assay (PLA) is a unique method in which single-stranded oligonucleotides are conjugated to affinity binders of proteins, followed by amplification of the signal by DNA polymerization and hybridization of complementary oligonucleotides labeled with fluorogenic or chromogenic readout. Here, a brief overview of the field of protein analysis describes the background and the initial development of the technique for the detection of protein–protein interactions via the proximity probes mentioned. In this context, PLA can constrain the general problem of cross-reactivity in protein detection by affinity binders, by ensuring that only cognate pairs of proximity probes result in a signal. Thereafter, this chapter deals mainly with derivatives methods and their applications, with a particular interest in improved specificity, application to various biological materials, and multiplexing. The method has been applied in situ and in solution, adapted for the detection of posttranslational modifications such as phosphorylation and interactions between proteins and specific DNA sequences, and multiplexed to a certain extent, which illustrates its versatility. A technique free from enzymatic reaction, the hybridization chain reaction, can be considered a cost-effective alternative particularly suitable to molecular diagnostics. Finally, we explore further development toward higher-level multiplexing and sensitivity. At this point it is not clear what level can be achieved by PLA, but the assay is compatible with a wide range of readout, including separate real-time amplification reactions and novel microfluidic read-out platforms.

  • 20.
    Chandran, Vineesh Indira
    et al.
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Welinder, Charlotte
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    de Oliveira, Kelin Goncalves
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Cerezo-Magana, Myriam
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Mansson, Ann-Sofie
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Johansson, Maria C.
    Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden.
    Marko-Varga, Gyorgy
    Lund Univ, Biomed Ctr, Clin Prot Sci & Imaging, Dept Biomed Engn, Lund, Sweden.
    Belting, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Lund Univ, Div Oncol & Pathol, Dept Clin Sci, Lund, Sweden;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    Global extracellular vesicle proteomic signature defines U87-MG glioma cell hypoxic status with potential implications for non-invasive diagnostics2019Inngår i: Journal of Neuro-Oncology, ISSN 0167-594X, E-ISSN 1573-7373, Vol. 144, nr 3, s. 477-488Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose Glioblastoma multiforme (GBM) is the most common and lethal of primary malignant brain tumors. Hypoxia constitutes a major determining factor for the poor prognosis of high-grade glioma patients, and is known to contribute to the development of treatment resistance. Therefore, new strategies to comprehensively profile and monitor the hypoxic status of gliomas are of high clinical relevance. Here, we have explored how the proteome of secreted extracellular vesicles (EVs) at the global level may reflect hypoxic glioma cells. Methods We have employed shotgun proteomics and label free quantification to profile EVs isolated from human high-grade glioma U87-MG cells cultured at normoxia or hypoxia. Parallel reaction monitoring was used to quantify the identified, hypoxia-associated EV proteins. To determine the potential biological significance of hypoxia-associated proteins, the cumulative Z score of identified EV proteins was compared with GBM subtypes from HGCC and TCGA databases. Results In total, 2928 proteins were identified in EVs, out of which 1654 proteins overlapped with the ExoCarta EV-specific database. We found 1034 proteins in EVs that were unique to the hypoxic status of U87-MG cells. We subsequently identified an EV protein signature, "HYPSIGNATURE", encompassing nine proteins that strongly represented the hypoxic situation and exhibited close proximity to the mesenchymal GBM subtype. Conclusions We propose, for the first time, an EV protein signature that could comprehensively reflect the hypoxic status of high-grade glioma cells. The presented data provide proof-of-concept for targeted proteomic profiling of glioma derived EVs, which should motivate future studies exploring its utility in non-invasive diagnosis and monitoring of brain tumor patients.

  • 21.
    Chandran, Vineesh Indira
    et al.
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Welinder, Charlotte
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden;Lund Univ, CEBMMS, Lund, Sweden.
    Mansson, Ann-Sofie
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Offer, Svenja
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Freyhult, Eva
    Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Pernemalm, Maria
    Karolinska Inst, Dept Oncol & Pathol, Solna, Sweden.
    Lund, Sigrid M.
    Aalborg Univ Hosp, Dept Clin Biochem, Aalborg, Denmark.
    Pedersen, Shona
    Aalborg Univ Hosp, Dept Clin Biochem, Aalborg, Denmark;Aalborg Univ, Fac Clin Med, Aalborg, Denmark.
    Lehtio, Janne
    Karolinska Inst, Dept Oncol & Pathol, Solna, Sweden.
    Marko-Varga, Gyorgy
    Lund Univ, CEBMMS, Lund, Sweden;Lund Univ, Dept Biomed Engn, Biomed Ctr, Clin Prot Sci & Imaging, Lund, Sweden.
    Johansson, Maria C.
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Englund, Elisabet
    Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden.
    Sundgren, Pia C.
    Lund Univ, Sect Diagnost Radiol, Dept Clin Sci, Lund, Sweden;Lund Univ, Lund BioImaging Ctr, Lund, Sweden;Skane Univ Hosp, Dept Med Imaging & Funct, Lund, Sweden.
    Belting, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Lund Univ, Sect Oncol & Pathol, Dept Clin Sci, Barngatan 2 B, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Hematol Oncol & Radiophys, Lund, Sweden.
    Ultrasensitive Immunoprofiling of Plasma Extracellular Vesicles Identifies Syndecan-1 as a Potential Tool for Minimally Invasive Diagnosis of Glioma2019Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 25, nr 10, s. 3115-3127Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose: Liquid biopsy has great potential to improve the management of brain tumor patients at high risk of surgery-associated complications. Here, the aim was to explore plasma extracellular vesicle (plEV) immunoprofiling as a tool for noninvasive diagnosis of glioma. Experimental Design: PlEV isolation and analysis were optimized using advanced mass spectrometry, nanoparticle tracking analysis, and electron microscopy. We then established a new procedure that combines size exclusion chromatography isolation and proximity extension assay-based ultrasensitive immunoprofiling of plEV proteins that was applied on a well-defined glioma study cohort (n = 82). Results: Among potential candidates, we for the first time identify syndecan-1 (SDC1) as a plEV constituent that can discriminate between high-grade glioblastoma multiforme (GBM, WHO grade IV) and low-grade glioma [LGG, WHO grade II; area under the ROC curve (AUC): 0.81; sensitivity: 71%; specificity: 91%]. These findings were independently validated by ELISA. Tumor SDC1 mRNA expression similarly discriminated between GBM and LGG in an independent glioma patient population from The Cancer Genome Atlas cohort (AUC: 0.91; sensitivity: 79%; specificity: 91%). In experimental studies with GBM cells, we show that SDC1 is efficiently sorted to secreted EVs. Importantly, we found strong support of plEV(SDC1) originating from GBM tumors, as plEVSDC1 correlated with SDC1 protein expression in matched patient tumors, and plEV(SDC1) was decreased postoperatively depending on the extent of surgery. Conclusions: Our studies support the concept of circulating plEVs as a tool for noninvasive diagnosis and monitoring of gliomas and should move this field closer to the goal of improving the management of cancer patients.

  • 22.
    Chantzi, Efthymia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Enarsson, Maria
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Segerman, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Gustafsson, Mats G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    COMBImage2: a parallel computational framework for higher-order drug combination analysis that includes automated plate design, matched filter based object counting and temporal data mining2019Inngår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 20, artikkel-id 304Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Pharmacological treatment of complex diseases using more than two drugs is commonplace in the clinic due to better efficacy, decreased toxicity and reduced risk for developing resistance. However, many of these higher-order treatments have not undergone any detailed preceding in vitro evaluation that could support their therapeutic potential and reveal disease related insights. Despite the increased medical need for discovery and development of higher-order drug combinations, very few reports from systematic large-scale studies along this direction exist. A major reason is lack of computational tools that enable automated design and analysis of exhaustive drug combination experiments, where all possible subsets among a panel of pre-selected drugs have to be evaluated.

    Results: Motivated by this, we developed COMBImage2, a parallel computational framework for higher-order drug combination analysis. COMBImage2 goes far beyond its predecessor COMBImage in many different ways. In particular, it offers automated 384-well plate design, as well as quality control that involves resampling statistics and inter-plate analyses. Moreover, it is equipped with a generic matched filter based object counting method that is currently designed for apoptotic-like cells. Furthermore, apart from higher-order synergy analyses, COMBImage2 introduces a novel data mining approach for identifying interesting temporal response patterns and disentangling higher- from lower- and single-drug effects.COMBImage2 was employed in the context of a small pilot study focused on the CUSP9v4 protocol, which is currently used in the clinic for treatment of recurrent glioblastoma. For the first time, all 246 possible combinations of order 4 or lower of the 9 single drugs consisting the CUSP9v4 cocktail, were evaluated on an in vitro clonal culture of glioma initiating cells.

    Conclusions: COMBImage2 is able to automatically design and robustly analyze exhaustive and in general higher-order drug combination experiments. Such a versatile video microscopy oriented framework is likely to enable, guide and accelerate systematic large-scale drug combination studies not only for cancer but also other diseases.

  • 23.
    Chantzi, Efthymia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin. Uppsala Univ, In Vitro Syst Pharmacol Facil, SciLifeLab Drug Discovery & Dev, Uppsala, Sweden.
    Niklasson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Segerman, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Gustafsson, Mats G
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    COMBImage: a modular parallel processing framework for pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies2018Inngår i: BMC Bioinformatics, ISSN 1471-2105, E-ISSN 1471-2105, Vol. 19, artikkel-id 453Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Large-scale pairwise drug combination analysis has lately gained momentum in drug discovery and development projects, mainly due to the employment of advanced experimental-computational pipelines. This is fortunate as drug combinations are often required for successful treatment of complex diseases. Furthermore, most new drugs cannot totally replace the current standard-of-care medication, but rather have to enter clinical use as add-on treatment. However, there is a clear deficiency of computational tools for label-free and temporal image-based drug combination analysis that go beyond the conventional but relatively uninformative end point measurements.

    Results: COMBImage is a fast, modular and instrument independent computational framework for in vitro pairwise drug combination analysis that quantifies temporal changes in label-free video microscopy movies. Jointly with automated analyses of temporal changes in cell morphology and confluence, it performs and displays conventional cell viability and synergy end point analyses. The image processing algorithms are parallelized using Google's MapReduce programming model and optimized with respect to method-specific tuning parameters. COMBImage is shown to process time-lapse microscopy movies from 384-well plates within minutes on a single quad core personal computer.This framework was employed in the context of an ongoing drug discovery and development project focused on glioblastoma multiforme; the most deadly form of brain cancer. Interesting add-on effects of two investigational cytotoxic compounds when combined with vorinostat were revealed on recently established clonal cultures of glioma-initiating cells from patient tumor samples. Therapeutic synergies, when normal astrocytes were used as a toxicity cell model, reinforced the pharmacological interest regarding their potential clinical use.

    Conclusions: COMBImage enables, for the first time, fast and optimized pairwise drug combination analyses of temporal changes in label-free video microscopy movies. Providing this jointly with conventional cell viability based end point analyses, it could help accelerating and guiding any drug discovery and development project, without use of cell labeling and the need to employ a particular live cell imaging instrument.

  • 24.
    Costa, Tania D. F.
    et al.
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    Zhuang, Ting
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden;Xinxiang Med Univ, Sch Lab Med, Henan Collaborat Innovat Ctr Mol Diag & Lab Med, Xinxiang 453003, Henan, Peoples R China.
    Lorent, Julie
    Karolinska Inst, Dept Oncol Pathol, SE-17177 Solna, Sweden.
    Turco, Emilia
    Univ Torino, Dept Genet Biol & Biochem, I-10126 Turin, Italy.
    Olofsson, Helene
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    Masia-Balague, Miriam
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    Zhao, Miao
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    Rabieifar, Parisa
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    Robertson, Neil
    Beatson Inst Canc Res Bearsden, Glasgow G61 1BD, Lanark, Scotland.
    Kuiper, Raoul
    Karolinska Inst, Dept Lab Med, SE-14157 Huddinge, Sweden.
    Sjölund, Jonas
    Lund Univ, Dept Lab Med, Div Translat Canc Res, SE-22381 Lund, Sweden.
    Spiess, Matthias
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    Hernandez-Varas, Pablo
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    Rabenhorst, Uta
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    Roswall, Pernilla
    Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, SE-17177 Solna, Sweden.
    Ma, Ran
    Karolinska Inst, Dept Oncol Pathol, SE-17177 Solna, Sweden.
    Gong, Xiaowei
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    Hartman, Johan
    Karolinska Inst, Dept Oncol Pathol, SE-17177 Solna, Sweden.
    Pietras, Kristian
    Lund Univ, Dept Lab Med, Div Translat Canc Res, SE-22381 Lund, Sweden;Karolinska Inst, Dept Med Biochem & Biophys, Div Vasc Biol, SE-17177 Solna, Sweden.
    Adams, Peter D.
    Beatson Inst Canc Res Bearsden, Glasgow G61 1BD, Lanark, Scotland;Univ Glasgow, Coll Med Vet & Life Sci, Inst Canc Sci, Glasgow G12 8QQ, Lanark, Scotland;Sanford Burnham Prebys Med Discovery Inst, 10901 North Torrey Pines Rd, La Jolla, CA 92037 USA.
    Defilippi, Paola
    Univ Torino, Dept Genet Biol & Biochem, I-10126 Turin, Italy.
    Stromblad, Staffan
    Karolinska Inst, Dept Biosci & Nutr, SE-14183 Huddinge, Sweden.
    PAK4 suppresses RELB to prevent senescence-like growth arrest in breast cancer2019Inngår i: Nature Communications, ISSN 2041-1723, E-ISSN 2041-1723, Vol. 10, artikkel-id 3589Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Overcoming cellular growth restriction, including the evasion of cellular senescence, is a hallmark of cancer. We report that PAK4 is overexpressed in all human breast cancer subtypes and associated with poor patient outcome. In mice, MMTV-PAK4 overexpression promotes spontaneous mammary cancer, while PAK4 gene depletion delays MMTV-PyMT driven tumors. Importantly, PAK4 prevents senescence-like growth arrest in breast cancer cells in vitro, in vivo and ex vivo, but is not needed in non-immortalized cells, while PAK4 overexpression in untransformed human mammary epithelial cells abrogates H-RAS-V12-induced senescence. Mechanistically, a PAK4 – RELB - C/EBPβ axis controls the senescence-like growth arrest and a PAK4 phosphorylation residue (RELB-Ser151) is critical for RELB-DNA interaction, transcriptional activity and expression of the senescence regulator C/EBPβ. These findings establish PAK4 as a promoter of breast cancer that can overcome oncogene-induced senescence and reveal a selective vulnerability of cancer to PAK4 inhibition.

  • 25.
    Darmanis, Spyros
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Gallant, Caroline Julie
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Marinescu, Voichita Dana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Niklasson, Mia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Segerman, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Flamourakis, Georgios
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Fredriksson, Simon
    Olink Biosci, S-75237 Uppsala, Sweden..
    Assarsson, Erika
    Olink Biosci, S-75237 Uppsala, Sweden..
    Lundberg, Martin
    Olink Biosci, S-75237 Uppsala, Sweden..
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Landegren, Ulf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells2016Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, nr 2, s. 380-389Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Significant advances have been made in methods to analyze genomes and transcriptomes of single cells, but to fully define cell states, proteins must also be accessed as central actors defining a cell's phenotype. Methods currently used to analyze endogenous protein expression in single cells are limited in specificity, throughput, or multiplex capability. Here, we present an approach to simultaneously and specifically interrogate large sets of protein and RNA targets in lysates from individual cells, enabling investigations of cell functions and responses. We applied our method to investigate the effects of BMP4, an experimental therapeutic agent, on early-passage glioblastoma cell cultures. We uncovered significant heterogeneity in responses to treatment at levels of RNA and protein, with a subset of cells reacting in a distinct manner to BMP4. Moreover, we found overall poor correlation between protein and RNA at the level of single cells, with proteins more accurately defining responses to treatment.

  • 26.
    Dijksterhuis, Jacomijn P.
    et al.
    Karolinska Inst, Sect Receptor Biol & Signaling, Deptartment Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Arthofer, Elisa
    Karolinska Inst, Sect Receptor Biol & Signaling, Deptartment Physiol & Pharmacol, S-17177 Stockholm, Sweden..
    Marinescu, Voichita D.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Ponten, Frederik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Mulder, Jan
    Karolinska Inst, Dept Neurosci, Sci Life Lab, S-17177 Stockholm, Sweden..
    Schulte, Gunnar
    Karolinska Inst, Sect Receptor Biol & Signaling, Deptartment Physiol & Pharmacol, S-17177 Stockholm, Sweden.;Masaryk Univ, Fac Sci, Inst Expt Biol, CS-61137 Brno, Czech Republic..
    High levels of WNT-5A in human glioma correlate with increased presence of tumor-associated microglia/monocytes2015Inngår i: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 339, nr 2, s. 280-288Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Malignant gliomas are among the most severe types of cancer, and the most common primary brain tumors. Treatment options are limited and the prognosis is poor. WNT-5A, a member of the WNT family of lipoglycoproteins, plays a role in oncogenesis and tumor progression in various cancers, whereas the role of WNT-5A in glioma remains obscure. Based on the role of WNT-5A as an oncogene, its potential to regulate microglia cells and the glioma-promoting capacities of microglia cells, we hypothesize that WNT-5A has a role in regulation of immune functions in glioma. We investigated WNT-5A expression by in silico analysis of the cancer genome atlas (TCGA) transcript profiling of human glioblastoma samples and immunohistochemistry experiments of human glioma tissue microarrays (TMA). Our results reveal higher WNT-5A protein levels and mRNA expression in a subgroup of gliomas (WNT-5A(high)) compared to non-malignant control brain tissue. Furthermore, we show a significant correlation between WNT-5A in the tumor and presence of major histocompatibility complex Class II-positive microglia/monocytes. Our data pinpoint a positive correlation between WNT-5A and a proinflammatory signature in glioma. We identify increased presence of microglia/monocytes as an important aspect in the inflammatory transformation suggesting a novel role for WNT-5A in human glioma.

  • 27.
    Doroszko, Milena
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Univ Turku, Inst Biomed, Turku, Finland.
    Chrusciel, Marcin
    Univ Turku, Inst Biomed, Turku, Finland.
    Stelmaszewska, Joanna
    Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    Slezak, Tomasz
    Univ Chicago, Dept Biochem & Mol Biol, Chicago, IL 60637 USA.
    Anisimowicz, Slawomir
    Ctr Gynecol & Reprod Endocrinol Artemida, Bialystok, Poland.
    Plöckinger, Ursula
    Charite Univ Med Berlin, Interdisciplinary Ctr Metab Endocrinol Diabet & M, Berlin, Germany.
    Quinkler, Marcus
    Endocrinol Charlottenburg, Berlin, Germany;Charite Univ Med Berlin, Charite Campus Mitte, Dept Clin Endocrinol, Berlin, Germany.
    Bonomi, Marco
    Univ Milan, Dept Clin Sci & Community Hlth, Milan, Italy.
    Wolczynski, Slawomir
    Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    Huhtaniemi, Ilpo
    Univ Turku, Inst Biomed, Turku, Finland;Imperial Coll London, Fac Med, Dept Surg & Canc, London, England.
    Toppari, Jorma
    Univ Turku, Inst Biomed, Turku, Finland;Turku Univ Hosp, Dept Pediat, Turku, Finland.
    Rahman, Nafis A.
    Univ Turku, Inst Biomed, Turku, Finland;Med Univ Bialystok, Dept Reprod & Gynecol Endocrinol, Bialystok, Poland.
    GnRH antagonist treatment of malignant adrenocortical tumors2019Inngår i: Endocrine-Related Cancer, ISSN 1351-0088, E-ISSN 1479-6821, Vol. 26, nr 1, s. 103-117Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Aberrantly expressed G protein-coupled receptors in tumors are considered as potential therapeutic targets. We analyzed the expressions of receptors of gonadotropin-releasing hormone (GNRHR), luteinizing hormone/chorionic gonadotropin (LHCGR) and follicle-stimulating hormone (FSHR) in human adrenocortical carcinomas and assessed their response to GnRH antagonist therapy. We further studied the effects of the GnRH antagonist cetrorelix acetate (CTX) on cultured adrenocortical tumor (ACT) cells (mouse C alpha 1 and Y-1, and human H295R), and in vivo in transgenic mice (SV40 T-antigen expression under inhibin a promoter) bearing Lhcgr and Gnrhr in ACT. Both models were treated with control (CT), CTX, human chorionic gonadotropin (hCG) or CTX+hCG, and their growth and transcriptional changes were analyzed. In situ hybridization and qPCR analysis of human adrenocortical carcinomas (n = 11-13) showed expression of GNRHR in 54/73%, LHCGR in 77/100% and FSHR in 0%, respectively. CTX treatment in vitro decreased cell viability and proliferation, and increased caspase 3/7 activity in all treated cells. In vivo, CTX and CTX+hCG (but not hCG alone) decreased ACT weights and serum LH and progesterone concentrations. CTX treatment downregulated the tumor markers Lhcgr and Gata4. Upregulated genes included Grb10, Rerg, Nfatc and Gnas, all recently found to be abundantly expressed in healthy adrenal vs ACT. Our data suggest that CTX treatment may improve the therapy of human adrenocortical carcinomas by direct action on GNRHR-positive cancer cells inducing apoptosis and/or reducing gonadotropin release, directing tumor cells towards a healthy adrenal gene expression profile.

  • 28.
    Enarsson, Mia
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Bergström, Tobias
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Sundström, Anders
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nyberg, Frida
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Haglund, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Westermark, Bengt
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Segerman, Bo
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Natl Vet Inst, Dept Microbiol, Uppsala, Sweden.
    Segerman, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala Univ, Dept Immunol Genet & Pathol, Sci Life Lab, Rudbeck Lab, Uppsala, Sweden;Uppsala Univ, Uppsala Univ Hosp, Dept Med Sci Canc Pharmacol & Computat Med, Uppsala, Sweden.
    Mesenchymal transition and increased therapy resistance of glioblastoma cells is related to astrocyte reactivity2019Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 249, nr 3, s. 295-307Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Grade IV astrocytoma/glioblastoma multiforme (GBM) is essentially incurable, partly due to its heterogenous nature, demonstrated even within the glioma-initiating cell (GIC) population. Increased therapy resistance of GICs is coupled to transition into a mesenchymal (MES) cell state. The GBM MES molecular signature displays a pronounced inflammatory character and its expression vary within and between tumors. Herein, we investigate how MES transition of GBM cells relates to inflammatory responses of normal astroglia. In response to CNS insults astrocytes enter a reactive cell state and participate in directing neuroinflammation and subsequent healing processes. We found that the MES signature show strong resemblance to gene programs induced in reactive astrocytes. Likewise, astrocyte reactivity gene signatures were enriched in therapy-resistant MES-like GIC clones. Variable expression of astrocyte reactivity related genes also largely defined intratumoral GBM cell heterogeneity at the single-cell level and strongly correlated with our previously defined therapy-resistance signature (based on linked molecular and functional characterization of GIC clones). In line with this, therapy-resistant MES-like GIC secreted immunoregulatory and tissue repair related proteins characteristic of astrocyte reactivity. Moreover, sensitive GIC clones could be made reactive through long-term exposure to the proinflammatory cytokine interleukin 1 beta (IL1 beta). IL1 beta induced a slow MES transition, increased therapy resistance, and a shift in DNA methylation profile towards that of resistant clones, which confirmed a slow reprogramming process. In summary, GICs enter through MES transition a reactive-astrocyte-like cell state, connected to therapy resistance. Thus, from a biological point of view, MES GICs would preferably be called 'reactive GICs'. The ability of GBM cells to mimic astroglial reactivity contextualizes the immunomodulatory and microenvironment reshaping abilities of GBM cells that generate a tumor-promoting milieu. This insight will be important to guide the development of future sensitizing therapies targeting treatment-resistant relapse-driving cell populations as well as enhancing the efficiency of immunotherapies in GBM. (c) 2019 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

  • 29.
    Ferrucci, Veronica
    et al.
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy;European Sch Mol Med SEMM, Milan, Italy.
    de Antonellis, Pasqualino
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy;Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
    Pennino, Francesco Paolo
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Asadzadeh, Fatemeh
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Virgilio, Antonella
    Univ Napoli Federico II, Dipartimento Farm, Naples, Italy.
    Montanaro, Donatella
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Galeone, Aldo
    Univ Napoli Federico II, Dipartimento Farm, Naples, Italy.
    Boffa, Iolanda
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Pisano, Ida
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Scognamiglio, Iolanda
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Navas, Luigi
    Univ Napoli Federico II, Dept Vet Med & Anim Prod, Naples, Italy.
    Diana, Donatella
    CNR, Ist Biostrutture & Bioimmagini, Naples, Italy.
    Pedone, Emilia
    CNR, Ist Biostrutture & Bioimmagini, Naples, Italy.
    Gargiulo, Sara
    CNR, Ist Biostrutture & Bioimmagini, Naples, Italy.
    Gramanzini, Matteo
    CNR, Ist Biostrutture & Bioimmagini, Naples, Italy.
    Brunetti, Arturo
    CEINGE Biotecnol Avanzate, Naples, Italy;Univ Napoli Federico II, Dipartimento Sci Biomed Avanzate, Naples, Italy.
    Danielson, Laura
    Inst Canc Res, Div Clin Studies, Sutton SM2 5NG, Surrey, England.
    Carotenuto, Marianeve
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Liguori, Lucia
    CEINGE Biotecnol Avanzate, Naples, Italy.
    Verrico, Antonio
    Osped Santobono Pausilipon, Paediat Neurosurg, Naples, Italy.
    Quaglietta, Lucia
    Osped Santobono Pausilipon, Paediat Neurosurg, Naples, Italy.
    Errico, Maria Elena
    Osped Santobono Pausilipon, Pathol Unit, Naples, Italy.
    Del Monaco, Valentina
    CEINGE Biotecnol Avanzate, Naples, Italy.
    D'Argenio, Valeria
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Tirone, Felice
    Fdn Santa Lucia, Natl Res Council, Inst Cell Biol & Neurobiol, Genet Control Dev URT, Rome, Italy.
    Mastronuzzi, Angela
    IRCCS Osped Pediat Bambino Gesu, Dipartimento Oncoematol, Rome, Italy.
    Donofrio, Vittoria
    Osped Santobono Pausilipon, Pathol Unit, Naples, Italy.
    Giangaspero, Felice
    Univ Roma La Sapienza, Dipartimento Sci Radiol Oncol & Anatomo Patol, Rome, Italy;IRCCS Neuromed, Pozzilli, Italy.
    Picard, Daniel
    Univ Hosp Dusseldorf, Dept Paediat Oncol Haematol & Clin Immunol, German Canc Consortium DKTK, Dusseldorf, Germany.
    Remke, Marc
    Univ Hosp Dusseldorf, Dept Paediat Oncol Haematol & Clin Immunol, German Canc Consortium DKTK, Dusseldorf, Germany.
    Garzia, Livia
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada;Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada.
    Daniels, Craig
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
    Delattre, Olivier
    PSL Res Univ, Inst Curie, Equipe Labellisue Ligue Canc, INSERM,U830, Paris, France.
    Johansson, Fredrik K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Weiss, William A.
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA USA.
    Salvatore, Francesco
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
    Fattorusso, Roberto
    Dipartimento Sci & Tecnol Ambientali, Biol & Farmaceut, Caserta, Italy.
    Chesler, Louis
    Inst Canc Res, Div Clin Studies, Sutton SM2 5NG, Surrey, England.
    Taylor, Michael D.
    Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada;Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada.
    Cinalli, Giuseppe
    Osped Santobono Pausilipon, Paediat Neurosurg, Naples, Italy.
    Zollo, Massimo
    Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy;European Sch Mol Med SEMM, Milan, Italy;Azienda Osped Univ Federico II, DAI Med Trasfus, Naples, Italy.
    Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1–TGF-β–OTX2–SNAIL via PTEN inhibitio2018Inngår i: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, nr 5, s. 1300-1319Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common ‘non-synonymous homozygous’ deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.

  • 30. Galli, Stephen J
    et al.
    Tsai, Mindy
    Marichal, Thomas
    Tchougounova, Elena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Reber, Laurent L
    Pejler, Gunnar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinsk biokemi och mikrobiologi.
    Approaches for analyzing the roles of mast cells and their proteases in vivo2015Inngår i: Advances in Immunology, ISSN 0065-2776, E-ISSN 1557-8445, Vol. 126, s. 45-127Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The roles of mast cells in health and disease remain incompletely understood. While the evidence that mast cells are critical effector cells in IgE-dependent anaphylaxis and other acute IgE-mediated allergic reactions seems unassailable, studies employing various mice deficient in mast cells or mast cell-associated proteases have yielded divergent conclusions about the roles of mast cells or their proteases in certain other immunological responses. Such "controversial" results call into question the relative utility of various older versus newer approaches to ascertain the roles of mast cells and mast cell proteases in vivo. This review discusses how both older and more recent mouse models have been used to investigate the functions of mast cells and their proteases in health and disease. We particularly focus on settings in which divergent conclusions about the importance of mast cells and their proteases have been supported by studies that employed different models of mast cell or mast cell protease deficiency. We think that two major conclusions can be drawn from such findings: (1) no matter which models of mast cell or mast cell protease deficiency one employs, the conclusions drawn from the experiments always should take into account the potential limitations of the models (particularly abnormalities affecting cell types other than mast cells) and (2) even when analyzing a biological response using a single model of mast cell or mast cell protease deficiency, details of experimental design are critical in efforts to define those conditions under which important contributions of mast cells or their proteases can be identified.

  • 31.
    Gezelius, E.
    et al.
    Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden.
    Bendahl, P. O.
    Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden.
    de Oliveira, K. Goncalves
    Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden.
    Ek, L.
    Skane Univ Hosp, Dept Resp Med, Entregatan 7, SE-22185 Lund, Sweden.
    Bergman, B.
    Sahlgrens Univ Hosp, Dept Resp Med, SE-41345 Gothenburg, Sweden.
    Sundberg, J.
    Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden.
    Strandberg, K.
    Lund Univ, Inst Lab Med, Dept Clin Chem, Inga Marie Nilssons Gata 53, SE-21428 Malmo, Sweden.
    Kraemer, R.
    Heidelberg Univ, Inorgan Chem Inst, Neuenheimer Feld 270, D-60129 Heidelberg, Germany.
    Belting, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Lund Univ, Div Oncol, Dept Clin Sci, Barngatan 4, SE-22185 Lund, Sweden;Skane Univ Hosp, Dept Hematol Radiophys & Oncol, Lasarettsgatan 23A, SE-22185 Lund, Sweden.
    Low-molecular-weight heparin adherence and effects on survival within a randomised phase III lung cancer trial (RASTEN)2019Inngår i: European Journal of Cancer, ISSN 0959-8049, E-ISSN 1879-0852, Vol. 118, s. 82-90Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Coagulation activation is a hallmark of cancer, and anticoagulants have shown tumour-inhibiting properties. However, recent trials have failed to demonstrate improved survival with low-molecular-weight heparin (LMWH) in cancer populations. This has raised the question of suboptimal adherence as a possible explanation for the lack of benefit. Still, there is no standardised method to directly monitor LMWH in patient plasma. Here, we directly determine LMWH levels in patients using the Heparin Red assay to objectively assess adherence and how this associates with the patient outcome in the RASTEN trial. Methods: RASTEN is a multicentre, randomised phase III trial investigating if the addition of LMWH to standard therapy can improve survival in small-cell lung cancer. LMWH was measured in plasma (N = 258) by the Heparin Red assay and compared with the anti-factor Xa (anti-FXa) activity assay. Results: Both methods could differentiate patients in the LMWH arm from the control arm and patients receiving therapeutic LMWH owing to thrombosis. Receiver Operating Characteristic (ROC) analysis yielded adherence rates of 85% for anti-FXa and 68% for Heparin Red. No survival benefits were found in the adherent subgroup compared with the control arm (hazard ratio [HR]: 1.26; 95% confidence interval [CI]: 0.95-1.67; P = 0.105 and HR: 1.19; 95% CI: 0.89-1.60; P = 0.248 for anti-FXa and Heparin Red, respectively). Heparin Red could define patients with high probability of adherence to LMWH treatment, which warrants prospective studies for further validation. Our finding that the LMWH-adherent subpopulation did not show improved survival excludes that the negative outcome of RASTEN was due to poor adherence. (C) 2019 The Authors. Published by Elsevier Ltd.

  • 32.
    Gezelius, Emelie
    et al.
    Lund Univ, Skane Univ Hosp, Dept Clin Sci, Oncol, Barngatan 4, SE-22185 Lund, Sweden.
    Belting, Mattias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Lund Univ, Skane Univ Hosp, Dept Clin Sci, Oncol, Barngatan 4, SE-22185 Lund, Sweden.
    Biomarkers of venous thromboembolism in cancer: a silent echo from local events?2019Inngår i: Biomarkers in Medicine, ISSN 1752-0363, E-ISSN 1752-0371, Vol. 13, nr 7, s. 507-509Artikkel i tidsskrift (Annet vitenskapelig)
  • 33.
    Giannuzzi, Diana
    et al.
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Marconato, Laura
    Ctr Oncol Vet, Bologna, Italy.
    Cascione, Luciano
    USI, IOR, Bellinzona, Switzerland;SIB, Lausanne, Switzerland.
    Comazzi, Stefano
    Univ Milan, Dept Vet Med, Milan, Italy.
    Elgendy, Ramy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Pegolo, Sara
    Univ Padua, Dept Agron Food Nat Resources Anim & Environm, Padua, Italy.
    Cecchinato, Alessio
    Univ Padua, Dept Agron Food Nat Resources Anim & Environm, Padua, Italy.
    Bertoni, Francesco
    USI, IOR, Bellinzona, Switzerland.
    Aresu, Luca
    Univ Turin, Dept Vet Sci, Turin, Italy.
    Ferraresso, Serena
    Univ Padua, Dept Comparat Biomed & Food Sci, Padua, Italy.
    Mutational landscape of canine B-cell lymphoma profiled at single nucleotide resolution by RNA-seq2019Inngår i: PLoS ONE, ISSN 1932-6203, E-ISSN 1932-6203, Vol. 14, nr 4, artikkel-id e0215154Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The genomic landscape in human B-cell lymphoma has revealed several somatic mutations and potentially relevant germline alterations affecting therapy and prognosis. Also, mutations originally described as somatic aberrations have been shown to confer cancer predisposition when occurring in the germline. The relevance of mutations in canine B-cell lymphoma is scarcely known and gene expression profiling has shown similar molecular signatures among different B-cell histotypes, suggesting other biological mechanisms underlining differences. Here, we present a highly accurate approach to identify single nucleotide variants (SNVs) in RNA-seq data obtained from 62 completely staged canine B-cell lymphomas and 11 normal B-cells used as controls. A customized variant discovery pipeline was applied and SNVs were found in tumors and differentiated for histotype. A number of known and not previously identified SNVs were significantly associated to MAPK signaling pathway, negative regulation of apoptotic process and cell death, B-cell activation, NF-kB and JAK-STAT signaling. Interestingly, no significant genetic fingerprints were found separating diffuse large B-cell lymphoma from indolent lymphomas suggesting that differences of genetic landscape are not the pivotal causative factor of indolent behavior. We also detected several variants in expressed regions of canine B-cell lymphoma and identified SNVs having a direct impact on genes. Using this brand-new approach the consequence of a gene variant is directly associated to expression. Further investigations are in progress to deeply elucidate the mechanisms by which altered genes pathways may drive lymphomagenesis and a higher number of cases is also demanded to confirm this evidence.

  • 34.
    Giannuzzi, Diana
    et al.
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Marconato, Laura
    Ctr Oncol Vet, Bologna, Italy.
    Elgendy, Ramy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Ferraresso, Serena
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Scarselli, Elisa
    Nouscom Srl, Rome, Italy.
    Fariselli, Piero
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Nicosia, Alfredo
    Nouscom AG, Basel, Switzerland;Univ Naples Federico II, Dept Mol Med & Med Biotechnol, Naples, Italy;CEINGE Biotecnol Avanzate Scarl, Naples, Italy.
    Pegolo, Sara
    Univ Padua, Dept Agron Food Nat Resources Anim & Environm, Padua, Italy.
    Leoni, Guido
    Nouscom Srl, Rome, Italy.
    Laganga, Paola
    Ctr Oncol Vet, Bologna, Italy.
    Leone, Vito F.
    Ctr Oncol Vet, Bologna, Italy.
    Giantin, Mery
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Troise, Fulvia
    Nouscom Srl, Rome, Italy.
    Dacasto, Mauro
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Aresu, Luca
    Univ Turin, Dept Vet Sci, Turin, Italy.
    Longitudinal transcriptomic and genetic landscape of radiotherapy response in canine melanoma2019Inngår i: Veterinary and Comparative Oncology, ISSN 1476-5810, E-ISSN 1476-5829, Vol. 17, nr 3, s. 308-316Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Canine malignant melanoma (MM) is a highly aggressive tumour with a low survival rate and represents an ideal spontaneous model for the human counterpart. Considerable progress has been recently obtained, but the therapeutic success for canine melanoma is still challenging. Little is known about the mechanisms beyond pathogenesis and melanoma development, and the molecular response to radiotherapy has never been explored before. A faster and deeper understanding of cancer mutational processes and developing mechanisms are now possible through next generation sequencing technologies. In this study, we matched whole exome and transcriptome sequencing in four dogs affected by MM at diagnosis and at disease progression to identify possible genetic mechanisms associated with therapy failure. According to previous studies, a genetic similarity between canine MM and its human counterpart was observed. Several somatic mutations were functionally related to MAPK, PI3K/AKT and p53 signalling pathways, but located in genes other than BRAF, RAS and KIT. At disease progression, several mutations were related to therapy effects. Natural killer cell-mediated cytotoxicity and several immune-system-related pathways resulted activated opening a new scenario on the microenvironment in this tumour. In conclusion, this study suggests a potential role of the immune system associated to radiotherapy in canine melanoma, but a larger sample size associated with functional studies are needed.

  • 35.
    Glimelius, Bengt
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Melin, Beatrice
    Umeå Univ, Dept Radiat Sci, Umeå.
    Enblad, Gunilla
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Beskow, Anna H.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Uppsala kliniska forskningscentrum (UCR).
    Ahlström, Håkan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Radiologi.
    Bill-Axelson, Anna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Birgisson, Helgi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Gastrointestinalkirurgi.
    Björ, Ove
    Umeå Univ, Dept Radiat Sci, Umeå.
    Edqvist, Per-Henrik D
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Hansson, Tony
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm.
    Hellman, Per
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Henriksson, Kerstin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Häggman, Michael
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Urologkirurgi.
    Höglund, Martin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Hematologi.
    Jonsson, Håkan
    Umeå Univ, Dept Radiat Sci, Umeå.
    Larsson, Chatarina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Lindman, Henrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ljuslinder, Ingrid
    Umeå Univ, Dept Radiat Sci, Umeå.
    Mindus, Stephanie
    Akad Sjukhuset, Lung & Allergy Clin, Uppsala.
    Nygren, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Ponten, Fredrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Riklund, Katrine
    Umeå Univ, Dept Radiat Sci, Umeå.
    Rosenquist, Richard
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    Sandin, Fredrik
    Uppsala Univ Hosp, RCC Uppsala Örebro, Uppsala.
    Schwenk, Jochen M.
    KTH Royal Inst Technol, Sch Biotechnol, Affin Prote, SciLifeLab, Solna.
    Stenling, Roger
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Stålberg, Karin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kvinnors och barns hälsa.
    Stålberg, Peter
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för kirurgiska vetenskaper, Endokrinkirurgi.
    Sundström, Christer
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi.
    Thellenberg Karlsson, Camilla
    Umeå Univ, Dept Radiat Sci, Umeå.
    Westermark, Bengt
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Bergh, Anders
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Claesson-Welsh, Lena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Vaskulärbiologi.
    Palmqvist, Richard
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Sjöblom, Tobias
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Experimentell och klinisk onkologi.
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.2018Inngår i: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, nr 2, s. 187-194Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Background: Progress in cancer biomarker discovery is dependent on access to high-quality biological materials and high-resolution clinical data from the same cases. To overcome current limitations, a systematic prospective longitudinal sampling of multidisciplinary clinical data, blood and tissue from cancer patients was therefore initiated in 2010 by Uppsala and Umeå Universities and involving their corresponding University Hospitals, which are referral centers for one third of the Swedish population.

    Material and Methods: Patients with cancer of selected types who are treated at one of the participating hospitals are eligible for inclusion. The healthcare-integrated sampling scheme encompasses clinical data, questionnaires, blood, fresh frozen and formalin-fixed paraffin-embedded tissue specimens, diagnostic slides and radiology bioimaging data.

    Results: In this ongoing effort, 12,265 patients with brain tumors, breast cancers, colorectal cancers, gynecological cancers, hematological malignancies, lung cancers, neuroendocrine tumors or prostate cancers have been included until the end of 2016. From the 6914 patients included during the first five years, 98% were sampled for blood at diagnosis, 83% had paraffin-embedded and 58% had fresh frozen tissues collected. For Uppsala County, 55% of all cancer patients were included in the cohort.

    Conclusions: Close collaboration between participating hospitals and universities enabled prospective, longitudinal biobanking of blood and tissues and collection of multidisciplinary clinical data from cancer patients in the U-CAN cohort. Here, we summarize the first five years of operations, present U-CAN as a highly valuable cohort that will contribute to enhanced cancer research and describe the procedures to access samples and data.

  • 36.
    Goroshchuk, Oksana
    et al.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Attarha, Sanaz
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Andersson, Sonia
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Mints, Miriam
    Karolinska Inst, S-10401 Stockholm, Sweden..
    PKN1 overexpression as a predictor of poor survival in endometrial cancer2016Inngår i: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 32, s. 117-117Artikkel i tidsskrift (Annet vitenskapelig)
  • 37.
    Heiland, Dieter H.
    et al.
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Ferrarese, Roberto
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Claus, Rainer
    Univ Freiburg, Med Ctr, Dept Hematol Oncol & Stem Cell Transplantat, Freiburg, Germany..
    Dai, Fangping
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Masilamani, Anie P.
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Kling, Eva
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Weyerbrock, Astrid
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    Kling, Teresia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Carro, Maria S.
    Univ Freiburg, Med Ctr, Dept Neurosurg, Freiburg, Germany.;Univ Freiburg, Fac Med, Freiburg, Germany..
    c-Jun-N-terminal phosphorylation regulates DNMT1 expression and genome wide methylation in gliomas2017Inngår i: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, nr 4, s. 6940-6954Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    High-grade gliomas (HGG) are the most common brain tumors, with an average survival time of 14 months. A glioma-CpG island methylator phenotype (G-CIMP), associated with better clinical outcome, has been described in low and high-grade gliomas. Mutation of IDH1 is known to drive the G-CIMP status. In some cases, however, the hypermethylation phenotype is independent of IDH1 mutation, suggesting the involvement of other mechanisms. Here, we demonstrate that DNMT1 expression is higher in low-grade gliomas compared to glioblastomas and correlates with phosphorylated c-Jun. We show that phospho-c-Jun binds to the DNMT1 promoter and causes DNA hypermethylation. Phospho-c-Jun activation by Anisomycin treatment in primary glioblastoma-derived cells attenuates the aggressive features of mesenchymal glioblastomas and leads to promoter methylation and downregulation of key mesenchymal genes (CD44, MMP9 and CHI3L1). Our findings suggest that phospho-c-Jun activates an important regulatory mechanism to control DNMT1 expression and regulate global DNA methylation in Glioblastoma.

  • 38. Hill, Rebecca M.
    et al.
    Kuijper, Sanne
    Lindsey, Janet C.
    Petrie, Kevin
    Schwalbe, Ed C.
    Barker, Karen
    Boult, Jessica K. R.
    Williamson, Daniel
    Ahmad, Zai
    Hallsworth, Albert
    Ryan, Sarra L.
    Poon, Evon
    Robinson, Simon P.
    Ruddle, Ruth
    Raynaud, Florence I.
    Howell, Louise
    Kwok, Colin
    Joshi, Abhijit
    Nicholson, Sarah Leigh
    Crosier, Stephen
    Ellison, David W.
    Wharton, Stephen B.
    Robson, Keith
    Michalski, Antony
    Hargrave, Darren
    Jacques, Thomas S.
    Pizer, Barry
    Bailey, Simon
    Swartling, Fredrik J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Weiss, William A.
    Chesler, Louis
    Clifford, Steven C.
    Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease2015Inngår i: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 27, nr 1, s. 72-84Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    We undertook a comprehensive clinical and biological investigation of serial medulloblastoma biopsies obtained at diagnosis and relapse. Combined MYC family amplifications and P53 pathway defects commonly emerged at relapse, and all patients in this group died of rapidly progressive disease postrelapse. To study this interaction, we investigated a transgenic model of MYCN-driven medulloblastoma and found spontaneous development of Trp53 inactivating mutations. Abrogation of p53 function in this model produced aggressive tumors that mimicked characteristics of relapsed human tumors with combined P53-MYC dysfunction. Restoration of p53 activity and genetic and therapeutic suppression of MYCN all reduced tumor growth and prolonged survival. Our findings identify P53-MYC interactions at medulloblastoma relapse as biomarkers of clinically aggressive disease that may be targeted therapeutically.

  • 39. Hill, Rebecca M.
    et al.
    Kuijper, Sanne
    Lindsey, Janet
    Schwalbe, Ed C.
    Barker, Karen
    Boult, Jessica
    Williamson, Daniel
    Ahmad, Zai
    Hallsworth, Albert
    Ryan, Sarra
    Poon, Evon
    Robinson, Simon
    Ruddle, Ruth
    Raynaud, Florence
    Howell, Louise
    Kwok, Colin
    Joshi, Abhijit
    Nicholson, Sarah
    Crosier, Stephen
    Wharton, Stephen
    Jacques, Tom
    Robson, Keith
    Michalski, Antony
    Hargrave, Darren
    Pizer, Barry
    Bailey, Simon
    Swartling, Fredrik J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Petrie, Kevin
    Weiss, William A.
    Chesler, Louis
    Clifford, Steve
    MYC and TP53 defects interact at medulloblastoma relapse to define rapidly progressive disease and can be targeted therapeutically2014Inngår i: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, nr 19Artikkel i tidsskrift (Annet vitenskapelig)
  • 40.
    Hoffman, Lindsey M.
    et al.
    Childrens Hosp Colorado, Aurora, CO USA;Univ Colorado Denver, Aurora, CO USA.
    van Zanten, Sophie E. M. Veldhuijzen
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Colditz, Niclas
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Baugh, Joshua
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Chaney, Brooklyn
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Hoffmann, Marion
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Lane, Adam
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Fuller, Christine
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Miles, Lili
    Nemours Childrens Hosp, Orlando, FL USA.
    Hawkins, Cynthia
    Hosp Sick Children, Toronto, ON, Canada.
    Bartels, Ute
    Hosp Sick Children, Toronto, ON, Canada.
    Bouffet, Eric
    Hosp Sick Children, Toronto, ON, Canada.
    Goldman, Stewart
    Ann & Robert H Lurie Childrens Hosp Chicago, Chicago, IL 60611 USA.
    Leary, Sarah
    Fred Hutchinson Canc Res Ctr, 1124 Columbia St, Seattle, WA 98104 USA;Univ Washington, Seattle Childrens Hosp, Seattle, WA 98195 USA.
    Foreman, Nicholas K.
    Childrens Hosp Colorado, Aurora, CO USA;Univ Colorado Denver, Aurora, CO USA.
    Packer, Roger
    Childrens Natl Hlth Syst, Washington, DC USA.
    Warren, Katherine E.
    NCI, Bethesda, MD 20892 USA.
    Broniscer, Alberto
    St Jude Childrens Res Hosp, 332 N Lauderdale St, Memphis, TN 38105 USA.
    Kieran, Mark W.
    Dana Farber Boston Childrens Canc & Blood Disorde, Boston, MA USA.
    Minturn, Jane
    Univ Penn, Perelman Sch Med, Philadelphia, PA 19104 USA;Childrens Hosp Philadelphia, Philadelphia, PA 19104 USA.
    Comito, Melanie
    Penn State Univ, Hershey, PA USA.
    Broxson, Emmett
    Wright State Univ, Dayton, OH 45435 USA;Childrens Med Ctr, Dayton, OH USA.
    Shih, Chie-Schin
    Indiana Univ, Indianapolis, IN 46204 USA.
    Khatua, Soumen
    Univ Texas MD Anderson Canc Ctr, Houston, TX 77030 USA.
    Chintagumpala, Murali
    Baylor Coll Med, Texas Childrens Canc Ctr, Houston, TX 77030 USA;Baylor Coll Med, Hematol Ctr, Houston, TX 77030 USA.
    Carret, Anne Sophie
    Ctr Hosp Univ St Justine, Montreal, PQ, Canada.
    Escorza, Nancy Yanez
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Hassall, Timothy
    Lady Cilento Childrens Hosp, Brisbane, Qld, Australia.
    Ziegler, David S.
    Sydney Childrens Hosp, Kids Canc Ctr, Randwick, NSW, Australia;Univ New South Wales, Sydney, NSW, Australia.
    Gottardo, Nicholas
    Princess Margaret Hosp Children, Perth, WA, Australia.
    Dholaria, Hetal
    Princess Margaret Hosp Children, Perth, WA, Australia.
    Doughman, Renee
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Benesch, Martin
    Med Univ Graz, Graz, Austria.
    Drissi, Rachid
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Nazarian, Javad
    Childrens Natl Med Ctr, Washington, DC 20010 USA.
    Jabado, Nada
    McGill Univ, Montreal, PQ, Canada.
    Boddaert, Nathalie
    Hop Necker Enfants Malad, Paris, France.
    Varlet, Pascale
    Univ Paris V Descartes, Sorbonne Paris Cite, Hop St Anne, Paris, France.
    Giraud, Geraldine
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France.
    Castel, David
    Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France.
    Puget, Stephanie
    Hop Necker Enfants Malad, Paris, France.
    Jones, Chris
    Inst Canc Res, Sutton, Surrey, England.
    Hulleman, Esther
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Modena, Piergiorgio
    St Anna Como Gen Hosp, Como, Italy.
    Giagnacovo, Marzia
    St Anna Como Gen Hosp, Como, Italy.
    Antonelli, Manila
    Sapienza Univ Rome, Rome, Italy.
    Pietsch, Torsten
    Univ Bonn, Med Ctr, Bonn, Germany.
    Gielen, Gerrit H.
    Univ Bonn, Med Ctr, Bonn, Germany.
    Jones, David T. W.
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany.
    Sturm, Dominik
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany;Heidelberg Univ Hosp, Heidelberg, Germany.
    Pfister, Stefan M.
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany;Heidelberg Univ Hosp, Heidelberg, Germany.
    Gerber, Nicolas U.
    Univ Childrens Hosp Zurich, Zurich, Switzerland.
    Grotzer, Michael A.
    Univ Childrens Hosp Zurich, Zurich, Switzerland.
    Pfaff, Elke
    German Consortium Translat Canc Res, Heidelberg, Germany;Natl Centrum Tumorerkrankungen Heidelberg, Hopp Childrens Canc Ctr, German Canc Res Ctr, Heidelberg, Germany;Heidelberg Univ Hosp, Heidelberg, Germany.
    von Bueren, Andre O.
    Univ Geneva, Geneva, Switzerland;Univ Hosp Geneva, Geneva, Switzerland.
    Hargrave, Darren
    Great Ormond St Hosp Sick Children, London, England.
    Solanki, Guirish A.
    Birmingham Womens & Childrens Hosp, Birmingham, W Midlands, England.
    Cvrlje, Filip Jadrijevic
    Childrens Hosp Zagreb, Zagreb, Croatia.
    Kaspers, Gertjan J. L.
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands;Childrens Hosp Zagreb, Zagreb, Croatia.
    Vandertop, William P.
    Acad Princess Maxima Ctr Pediat Oncol, Utrecht, Netherlands.
    Grill, Jacques
    Univ Paris Saclay, Univ Paris Sud, Gustave Roussy, Villejuif, France.
    Bailey, Simon
    Royal Victoria Infirm, Great North Childrens Hosp, Victoria Wing, Newcastle Upon Tyne, Tyne & Wear, England.
    Biassoni, Veronica
    Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy.
    Massimino, Maura
    Ist Nazl Tumori, Fdn Ist Ricovero & Cura Carattere Sci, Milan, Italy.
    Calmon, Raphael
    Hop Necker Enfants Malad, Paris, France.
    Sanchez, Esther
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Bison, Brigitte
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Warmuth-Metz, Monika
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Leach, James
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Jones, Blaise
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    van Vuurden, Dannis G.
    Vrije Univ, Univ Med Ctr, Amsterdam, Netherlands.
    Kramm, Christof M.
    Univ Med Ctr Goettingen, Goettingen, Netherlands.
    Fouladi, Maryam
    Cincinnati Childrens Hosp Med Ctr, 3333 Burnet Ave, Cincinnati, OH 45229 USA.
    Clinical, Radiologic, Pathologic, and Molecular Characteristics of Long-Term Survivors of Diffuse Intrinsic Pontine Glioma (DIPG): A Collaborative Report From the International and European Society for Pediatric Oncology DIPG Registries2018Inngår i: Journal of Clinical Oncology, ISSN 0732-183X, E-ISSN 1527-7755, Vol. 36, nr 19, s. 1963-1972Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Purpose

    Diffuse intrinsic pontine glioma (DIPG) is a brainstem malignancy with a median survival of < 1 year. The International and European Society for Pediatric Oncology DIPG Registries collaborated to compare clinical, radiologic, and histomolecular characteristics between short-term survivors (STSs) and long-term survivors (LTSs).

    Materials and Methods

    Data abstracted from registry databases included patients from North America, Australia, Germany, Austria, Switzerland, the Netherlands, Italy, France, the United Kingdom, and Croatia.

    Results

    Among 1,130 pediatric and young adults with radiographically confirmed DIPG, 122 (11%) were excluded. Of the 1,008 remaining patients, 101 (10%) were LTSs (survival 2 years). Median survival time was 11 months (interquartile range, 7.5 to 16 months), and 1-, 2-, 3-, 4-, and 5-year survival rates were 42.3% (95% CI, 38.1% to 44.1%), 9.6% (95% CI, 7.8% to 11.3%), 4.3% (95% CI, 3.2% to 5.8%), 3.2% (95% CI, 2.4% to 4.6%), and 2.2% (95% CI, 1.4% to 3.4%), respectively. LTSs, compared with STSs, more commonly presented at age < 3 or > 10 years (11% v 3% and 33% v 23%, respectively; P < .001) and with longer symptom duration (P < .001). STSs, compared with LTSs, more commonly presented with cranial nerve palsy (83% v 73%, respectively; P = .008), ring enhancement (38% v 23%, respectively; P = .007), necrosis (42% v 26%, respectively; P = .009), and extrapontine extension (92% v 86%, respectively; P = .04). LTSs more commonly received systemic therapy at diagnosis (88% v 75% for STSs; P = .005). Biopsies and autopsies were performed in 299 patients (30%) and 77 patients (10%), respectively; 181 tumors (48%) were molecularly characterized. LTSs were more likely to harbor a HIST1H3B mutation (odds ratio, 1.28; 95% CI, 1.1 to 1.5; P = .002).

    Conclusion

    We report clinical, radiologic, and molecular factors that correlate with survival in children and young adults with DIPG, which are important for risk stratification in future clinical trials.

  • 41.
    Huang, Miller
    et al.
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
    Tailor, Jignesh
    Univ Cambridge, MRC Stem Cell Inst, Wellcome Trust, Tennis Court Rd, Cambridge CB2 1QR, England;Inst Canc Res, London SM2 5NG, England;Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada;Hosp Sick Children, Div Neurosurg, Toronto, ON, Canada.
    Zhen, Qiqi
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
    Gillmor, Aaron H.
    Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada;Univ Calgary, Charbonneau Canc Inst, Calgary, AB, Canada;Alberta Childrens Prov Gen Hosp, Res Inst, Calgary, AB, Canada.
    Miller, Matthew L.
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
    Weishaupt, Holger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Chen, Justin
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Zheng, Tina
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
    Nash, Emily K.
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
    McHenry, Lauren K.
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
    An, Zhenyi
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
    Ye, Fubaiyang
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
    Takashima, Yasuhiro
    Univ Cambridge, MRC Stem Cell Inst, Wellcome Trust, Tennis Court Rd, Cambridge CB2 1QR, England.
    Clarke, James
    Univ Cambridge, MRC Stem Cell Inst, Wellcome Trust, Tennis Court Rd, Cambridge CB2 1QR, England.
    Ayetey, Harold
    Univ Cambridge, MRC Stem Cell Inst, Wellcome Trust, Tennis Court Rd, Cambridge CB2 1QR, England.
    Cavalli, Florence Mg
    Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada;Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
    Luu, Betty
    Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada;Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
    Moriarity, Branden S.
    Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA;Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA;Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA.
    Ilkhanizadeh, Shirin
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
    Chavez, Lukas
    Hopp Childrens Canc Ctr KiTZ, Heidelberg, Germany;German Canc Consortium DKTK, Div Pediat Neurooncol, German Canc Res Ctr DKFZ, Heidelberg, Germany.
    Yu, Chunying
    Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada.
    Kurian, Kathreena M.
    Univ Bristol, Southmead Hosp, Inst Clin Neurosci, Level 1,Learning & Res Bldg, Bristol BS10 5NB, Avon, England.
    Magnaldo, Thierry
    Nice UMR CNRS 7284 INSERM U1081 UNS UCA, Inst Res Canc & Aging, Nice, France.
    Sevenet, Nicolas
    Univ Bordeaux, Inst Bergonie, 229 Cours Argonne, F-33076 Bordeaux, France;Univ Bordeaux, INSERM U1218, 229 Cours Argonne, F-33076 Bordeaux, France.
    Koch, Philipp
    Heidelberg Univ, Cent Inst Mental Hlth, Med Fac Mannheim, Mannheim, Germany;Hector Inst Translat Brain Res HITBR gGmbH, Mannheim, Germany;German Canc Res Ctr, Heidelberg, Germany.
    Pollard, Steven M.
    Univ Edinburgh, MRC Ctr Regenerat Med, Edinburgh, Midlothian, Scotland;Univ Edinburgh, Canc Res UK Edinburgh Ctr, Edinburgh, Midlothian, Scotland.
    Dirks, Peter
    Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada;Hosp Sick Children, Div Neurosurg, Toronto, ON, Canada;Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
    Snyder, Michael P.
    Stanford Univ, Dept Genet, Sch Med, Stanford, CA 94305 USA.
    Largaespada, David A.
    Univ Minnesota, Dept Pediat, Minneapolis, MN 55455 USA;Univ Minnesota, Ctr Genome Engn, Minneapolis, MN 55455 USA;Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN 55455 USA.
    Cho, Yoon Jae
    Oregon Hlth & Sci Univ, Dept Pediat, Div Pediat Neurol, 3181 Sw Sam Jackson Pk Rd, Portland, OR 97201 USA;Oregon Hlth & Sci Univ, Dept Pediat, Pape Family Pediat Res Inst, 3181 Sw Sam Jackson Pk Rd, Portland, OR 97201 USA;Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA.
    Phillips, Joanna J.
    Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA 94158 USA;Univ Calif San Francisco, Dept Pathol, San Francisco, CA 94158 USA.
    Johansson Swartling, Fredrik
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Morrissy, A. Sorana
    Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada;Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada;Univ Calgary, Charbonneau Canc Inst, Calgary, AB, Canada;Alberta Childrens Prov Gen Hosp, Res Inst, Calgary, AB, Canada;Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
    Kool, Marcel
    Hopp Childrens Canc Ctr KiTZ, Heidelberg, Germany;German Canc Consortium DKTK, Div Pediat Neurooncol, German Canc Res Ctr DKFZ, Heidelberg, Germany.
    Pfister, Stefan M.
    Hopp Childrens Canc Ctr KiTZ, Heidelberg, Germany;German Canc Consortium DKTK, Div Pediat Neurooncol, German Canc Res Ctr DKFZ, Heidelberg, Germany;Heidelberg Univ Hosp, Dept Pediat Hematol & Oncol, Heidelberg, Germany.
    Taylor, Michael D.
    Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada;Hosp Sick Children, Div Neurosurg, Toronto, ON, Canada;Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada;Univ Toronto, Dept Lab Med & Pathobiol, Toronto, ON, Canada.
    Smith, Austin
    Univ Cambridge, MRC Stem Cell Inst, Wellcome Trust, Tennis Court Rd, Cambridge CB2 1QR, England.
    Weiss, William A.
    Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA;Univ Calif San Francisco, Res Ctr, Dept Pediat, San Francisco, CA 94158 USA;Univ Calif San Francisco, Res Ctr, Dept Neurosurg, San Francisco, CA 94158 USA;Univ Calif San Francisco, Res Ctr, Dept Brain Tumor, San Francisco, CA 94158 USA.
    Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis2019Inngår i: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 25, nr 3, s. 433-+Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Human neural stem cell cultures provide progenitor cells that are potential cells of origin for brain cancers. However, the extent to which genetic predisposition to tumor formation can be faithfully captured in stem cell lines is uncertain. Here, we evaluated neuroepithelial stem (NES) cells, representative of cerebellar progenitors. We transduced NES cells with MYCN, observing medulloblastoma upon orthotopic implantation in mice. Significantly, transcriptomes and patterns of DNA methylation from xenograft tumors were globally more representative of human medulloblastoma compared to a MYCN-driven genetically engineered mouse model. Orthotopic transplantation of NES cells generated from Gorlin syndrome patients, who are predis- posed to medulloblastoma due to germline-mutated PTCH1, also generated medulloblastoma. We engineered candidate cooperating mutations in Gorlin NES cells, with mutation of DDX3X or loss of GSE1 both accelerating tumorigenesis. These findings demonstrate that human NES cells provide a potent experimental resource for dissecting genetic causation in medulloblastoma.

  • 42.
    Hutter, Sonja
    et al.
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Bolin, Sara
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Weishaupt, Holger
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Johansson, Fredrik K.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Modeling and Targeting MYC Genes in Childhood Brain Tumors2017Inngår i: Genes, ISSN 2073-4425, E-ISSN 2073-4425, Vol. 8, nr 4, artikkel-id 107Artikkel, forskningsoversikt (Fagfellevurdert)
    Abstract [en]

    Brain tumors are the second most common group of childhood cancers, accounting for about 20%-25% of all pediatric tumors. Deregulated expression of the MYC family of transcription factors, particularly c-MYC and MYCN genes, has been found in many of these neoplasms, and their expression levels are often correlated with poor prognosis. Elevated c-MYC/MYCN initiates and drives tumorigenesis in many in vivo model systems of pediatric brain tumors. Therefore, inhibition of their oncogenic function is an attractive therapeutic target. In this review, we explore the roles of MYC oncoproteins and their molecular targets during the formation, maintenance, and recurrence of childhood brain tumors. We also briefly summarize recent progress in the development of therapeutic approaches for pharmacological inhibition of MYC activity in these tumors.

  • 43.
    Iannaccone, Marco
    et al.
    Univ Teramo, Fac Biosci & Technol Food Agr & Environm, Via R Balzarini 1, I-64100 Teramo, Italy.
    Elgendy, Ramy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Giantin, Mery
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Martino, Camillo
    Univ Perugia, Dept Vet Med, Via S Costanzo 4, I-06126 Perugia, Italy.
    Giansante, Daniele
    Ist Zooprofilatt Sperimentale Abruzzo & Molise G, I-64100 Campo Boario, Teramo, Italy.
    Ianni, Andrea
    Univ Teramo, Fac Biosci & Technol Food Agr & Environm, Via R Balzarini 1, I-64100 Teramo, Italy.
    Dacasto, Mauro
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Padua, Italy.
    Martino, Giuseppe
    Univ Teramo, Fac Biosci & Technol Food Agr & Environm, Via R Balzarini 1, I-64100 Teramo, Italy.
    RNA Sequencing-Based Whole-Transcriptome Analysis of Friesian Cattle Fed with Grape Pomace-Supplemented Diet2018Inngår i: Animals, ISSN 2076-2615, E-ISSN 2076-2615, Vol. 8, nr 11, artikkel-id 188Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Grape pomace (GPO), the main by-product of the wine making process, is a rich source of polyphenols with potent antioxidant properties. Recently, GPO has emerged as a potential feed additive in livestock nutrition, with several reports describing its beneficial effects on animals' overall health status or production traits. However, little is known about it from a molecular biology standpoint. In the present study, we report the first RNA sequencing-based whole-transcriptome profiling of Friesian calves fed with a GPO-supplemented diet. We identified 367 differentially expressed genes (p < 0.05) in the GPO-supplemented calves (n = 5), when compared with unsupplemented control group (n = 5). The pathway analysis showed that cholesterol lipid biosynthesis' was the most negatively-enriched (p < 0.001) pathway in the GPO-supplemented animals. In specific terms, five important genes coding for cholesterol biosynthesis enzymes, namely the Farnesyl-diphosphate Farnesyltransferase 1 (FDFT-1), Squalene Epoxidase (SQLE), NAD(P)-dependent Steroid Dehydrogenase-like (NSDHL), Methylsterol Monooxygenase (MSMO)-1, and Sterol-C5-desaturase (SC5D), two major transcription factors (the Sterol Regulatory Element-binding Transcription Factor 1 and 2), as well as the Low-Density Lipoprotein Receptor (LDLR), were all downregulated following GPO supplementation. Such an effect was mirrored by a reduction of blood cholesterol levels (p = 0.07) and a lowered (p < 0.001) Malondialdehyde (lipid oxidation marker) level in carcasses. We provide evidence on the effects of GPO-supplemented diets on the whole-transcriptome signature in veal calves, which mainly reflects an antioxidant activity.

  • 44.
    Iannaccone, Marco
    et al.
    Univ Teramo, Fac Biosci & Technol Food Agr & Environm, Via R Balzarini 1, I-64100 Teramo, Italy.
    Ianni, Andrea
    G dAnnunzio Univ Chieti Pescara, Dept Med Oral & Biotechnol Sci, Via Vestini 31, I-66100 Chieti, Italy.
    Elgendy, Ramy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Martino, Camillo
    Ist Zooprofilatt Sperimentale Abruzzo & Molise G, Via Campo Boario, I-64100 Teramo, Italy.
    Giantin, Mery
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Legnaro, PD, Italy.
    Cerretani, Lorenzo
    Pizzoli SPA, Via Zenzalino Nord, I-400541 Budrio, BO, Italy.
    Dacasto, Mauro
    Univ Padua, Dept Comparat Biomed & Food Sci, Viale Univ 16, I-35020 Legnaro, PD, Italy.
    Martino, Giuseppe
    Univ Teramo, Fac Biosci & Technol Food Agr & Environm, Via R Balzarini 1, I-64100 Teramo, Italy.
    Iodine Supplemented Diet Positively Affect Immune Response and Dairy Product Quality in Fresian Cow2019Inngår i: Animals, ISSN 2076-2615, E-ISSN 2076-2615, Vol. 9, nr 11, artikkel-id 866Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Simple Summary: Iodine represents an important micronutrient and plays a fundamental role in animal biology. This trace element is currently supplied to animal diet to investigate its potential effects on productive and reproductive performances. However, little is known about its role in the regulation of gene expression in ruminants. In this study, the dietary iodine supplementation in dairy cows showed effective modification of the expression of several molecular targets, with an improvement of the pathways involved in immune response and oxidative stress and undoubted positive repercussions on animal health. Abstract: The effects of iodine supplementation on the whole-transcriptome of dairy cow using RNA sequencing has been investigated in this study. Iodine did not influence the milk composition, while an improvement was observed in the immune response as well as in the quality of dairy product. Indeed, the iodine intake specifically influenced the expression of 525 genes and the pathway analysis demonstrated that the most affected among them were related to immune response and oxidative stress. As a consequence, we indirectly showed a better response to bacterial infection because of the reduction of somatic cell counts; furthermore, an improvement of dairy product quality was observed since lipid oxidation reduced in fresh cheese. Such findings, together with the higher milk iodine content, clearly demonstrated that iodine supplementation in dairy cow could represent a beneficial practice to preserve animal health and to improve the nutraceutical properties of milk and its derived products.

  • 45.
    Jiang, Yiwen
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Med Biochem & Biophys, S-17177 Stockholm, Sweden..
    Marinescu, Voichita Dana
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Xie, Yuan
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Jarvius, Malin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Maturi, Naga Prathyusha
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Haglund, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Olofsson, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Lindberg, Nanna
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Olofsson, Tommie
    Natl Board Forens Med, Dept Forens Med, Box 1024, S-75140 Uppsala, Sweden..
    Leijonmarck, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap.
    Hesselager, Göran
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för neurovetenskap, Neurokirurgi.
    Alafuzoff, Irina
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Klinisk och experimentell patologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Fryknäs, Mårten
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Larsson, Rolf
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för medicinska vetenskaper, Cancerfarmakologi och beräkningsmedicin.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Glioblastoma Cell Malignancy and Drug Sensitivity Are Affected by the Cell of Origin2017Inngår i: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 18, nr 4, s. 977-990Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    The identity of the glioblastoma (GBM) cell of origin and its contributions to disease progression and treatment response remain largely unknown. We have analyzed how the phenotypic state of the initially transformed cell affects mouse GBM development and essential GBM cell (GC) properties. We find that GBM induced in neural stem-cell-like glial fibrillary acidic protein (GFAP)-expressing cells in the subventricular zone of adult mice shows accelerated tumor development and produces more malignant GCs (mGC1GFAP) that are less resistant to cancer drugs, compared with those originating from more differentiated nestin- (mGC2NES) or 2,'3'-cyclic nucleotide 3'-phosphodiesterase (mGC3CNP)-expressing cells. Transcriptome analysis of mouse GCs identified a 196 mouse cell origin (MCO) gene signature that was used to partition 61 patient-derived GC lines. Human GC lines that clustered with the mGC1GFAP cells were also significantly more self-renewing, tumorigenic, and sensitive to cancer drugs compared with those that clustered with mouse GCs of more differentiated origin.

  • 46.
    Jimenez-Pascual, Ana
    et al.
    Cardiff Univ, European Canc Stem Cell Res Inst, Sch Biosci, Cardiff, S Glam, Wales.
    Hale, James S.
    Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA; Case Comprehens Canc Ctr, Cleveland, OH USA.
    Kordowski, Anja
    Cardiff Univ, European Canc Stem Cell Res Inst, Sch Biosci, Cardiff, S Glam, Wales.
    Pugh, Jamie
    Cardiff Univ, European Canc Stem Cell Res Inst, Sch Biosci, Cardiff, S Glam, Wales.
    Silver, Daniel J.
    Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA; Case Comprehens Canc Ctr, Cleveland, OH USA.
    Bayik, Defne
    Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA; Case Comprehens Canc Ctr, Cleveland, OH USA.
    Roversi, Gustavo
    Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA.
    Alban, Tyler J.
    Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA; Case Comprehens Canc Ctr, Cleveland, OH USA; Case Western Reserve Univ, Dept Mol Med, Cleveland Clin, Lerner Coll Med, Cleveland, OH USA.
    Rao, Shilpa
    Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA; Case Comprehens Canc Ctr, Cleveland, OH USA.
    Chen, Rui
    Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA.
    McIntyre, Thomas M.
    Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA; Case Comprehens Canc Ctr, Cleveland, OH USA; Case Western Reserve Univ, Dept Mol Med, Cleveland Clin, Lerner Coll Med, Cleveland, OH USA.
    Colombo, Giorgio
    Univ Pavia, Dept Chem, Milan, Italy; ICRM CNR, Inst Mol Recognit Chem, Milan, Italy.
    Taraboletti, Giulia
    Ist Ric Farmacol Mario Negri IRCCS, Bergamo, Italy.
    Holmberg, Karl O.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Uppsala universitet, Science for Life Laboratory, SciLifeLab.
    Forsberg Nilsson, Karin
    Uppsala universitet, Science for Life Laboratory, SciLifeLab. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Lathia, Justin D.
    Cleveland Clin, Lerner Res Inst, Dept Cardiovasc & Metab Sci, Cleveland, OH USA; Case Comprehens Canc Ctr, Cleveland, OH USA; Case Western Reserve Univ, Dept Mol Med, Cleveland Clin, Lerner Coll Med, Cleveland, OH USA.
    Siebzehnrubl, Florian A.
    Cardiff Univ, European Canc Stem Cell Res Inst, Sch Biosci, Cardiff, S Glam, Wales.
    ADAMDEC1 Maintains a Growth Factor Signaling Loop in Cancer Stem Cells2019Inngår i: Cancer Discovery, ISSN 2159-8274, E-ISSN 2159-8290, Vol. 9, nr 11, s. 1574-1589Artikkel i tidsskrift (Fagfellevurdert)
    Abstract [en]

    Glioblastomas (GBM) are lethal brain tumors where poor outcome is attributed to cellular heterogeneity, therapeutic resistance, and a highly infiltrative nature. These characteristics are preferentially linked to GBM cancer stem cells (GSC), but how GSCs maintain their stemness is incompletely understood and the subject of intense investigation. Here, we identify a novel signaling loop that induces and maintains GSCs consisting of an atypical metalloproteinase, ADAMDEC1, secreted by GSCs. ADAMDEC1 rapidly solubilizes FGF2 to stimulate FGFR1 expressed on GSCs. FGFR1 signaling induces upregulation of ZEB1 via ERK1/2 that regulates ADAMDEC1 expression through miR-203, creating a positive feedback loop. Genetic or pharmacologic targeting of components of this axis attenuates self-renewal and tumor growth. These findings reveal a new signaling axis for GSC maintenance and highlight ADAMDEC1 and FGFR1 as potential therapeutic targets in GBM.

    Significance: Cancer stem cells (CSC) drive tumor growth in many cancers including GBM. We identified a novel sheddase, ADAMDEC1, which initiates an FGF autocrine loop to promote stemness in CSCs. This loop can be targeted to reduce GBM growth.

  • 47.
    Johansson, Patrik
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Large scale integration and interactive exploration of cancer data – with applications to glioblastoma2018Doktoravhandling, med artikler (Annet vitenskapelig)
    Abstract [en]

    Glioblastoma is the most common malignant brain tumor, with a median survival of approximately 15 months. The standard of care treatment consists of surgical resection followed by radiotherapy and chemotherapy, where chemotherapy only prolongs survival by approximately 3 months. There is therefore an urgent need for new approaches to better understand the molecular vulnerabilities of glioblastoma. To this end, we have conducted four interdisciplinary studies.

    In study 1 we develop a method for efficiently constructing and exploring large integrative network models that include multiple cohorts and multiple types of molecular data. We apply this method to 8 cancers from The Cancer Genome Atlas (TCGA) and make the integrative network available for exploration and visualization through a custom web interface.

    In study 2 we establish a biobank of 48 patient derived glioblastoma cell cultures called the Human Glioma Cell Culture (HGCC) resource. We show that the HGCC cell cultures represent all transcriptional subtypes, carry genomic aberrations typical of glioblastoma, and initiate tumors in vivo. The HGCC is an open resource for translational glioblastoma research, made available through hgcc.se.

    In study 3 we extend the analysis of HGCC cell cultures both in terms of number (to over 100) and in terms of data types (adding mutation, methylation and drug response data). Large-scale drug profiling starting from over 1500 compounds identified two distinct groups of cell cultures defined by vulnerability to proteasome inhibition, p53/p21 activity, stemness and protein turnover. By applying machine learning methods to the combined drug profiling and matched genomics data we construct a first network of predictive biomarkers.

    In study 4 we use the methods developed in study 1 applied to the data generated in studies 2 and 3 to construct an integrative network model of HGCC and glioblastoma data from TCGA. We present an interactive method for exploring this network based on searching for network patterns representing specific hypotheses defined by the user.

    In conclusion, this thesis combines the development of integrative models with applications to novel data relevant for translational glioblastoma research. This work highlights several potentially therapeutically relevant aspects, and paves a path towards more comprehensive and informative models of glioblastoma.

    Delarbeid
    1. Efficient exploration of pan-cancer networks by generalized covariance selection and interactive web content
    Åpne denne publikasjonen i ny fane eller vindu >>Efficient exploration of pan-cancer networks by generalized covariance selection and interactive web content
    Vise andre…
    2015 (engelsk)Inngår i: Nucleic Acids Research, ISSN 0305-1048, E-ISSN 1362-4962, Vol. 43, nr 15, artikkel-id e98Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Statistical network modeling techniques are increasingly important tools to analyze cancer genomics data. However, current tools and resources are not designed to work across multiple diagnoses and technical platforms, thus limiting their applicability to comprehensive pan-cancer datasets such as The Cancer Genome Atlas (TCGA). To address this, we describe a new data driven modeling method, based on generalized Sparse Inverse Covariance Selection (SICS). The method integrates genetic, epigenetic and transcriptional data from multiple cancers, to define links that are present in multiple cancers, a subset of cancers, or a single cancer. It is shown to be statistically robust and effective at detecting direct pathway links in data from TCGA. To facilitate interpretation of the results, we introduce a publicly accessible tool ( ext-link-type="uri" xlink:href="http://cancerlandscapes.org/">cancerlandscapes.org), in which the derived networks are explored as interactive web content, linked to several pathway and pharmacological databases. To evaluate the performance of the method, we constructed a model for eight TCGA cancers, using data from 3900 patients. The model rediscovered known mechanisms and contained interesting predictions. Possible applications include prediction of regulatory relationships, comparison of network modules across multiple forms of cancer and identification of drug targets.

    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-264636 (URN)10.1093/nar/gkv413 (DOI)000361303300003 ()25953855 (PubMedID)
    Forskningsfinansiär
    Swedish Research CouncilSwedish Cancer SocietySwedish Childhood Cancer Foundation
    Tilgjengelig fra: 2015-10-23 Laget: 2015-10-15 Sist oppdatert: 2018-02-04bibliografisk kontrollert
    2. The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes
    Åpne denne publikasjonen i ny fane eller vindu >>The Human Glioblastoma Cell Culture Resource: Validated Cell Models Representing All Molecular Subtypes
    Vise andre…
    2015 (engelsk)Inngår i: EBioMedicine, E-ISSN 2352-3964, Vol. 2, nr 10, s. 1351-1363Artikkel i tidsskrift (Fagfellevurdert) Published
    Abstract [en]

    Glioblastoma (GBM) is the most frequent and malignant form of primary brain tumor. GBM is essentially incurable and its resistance to therapy is attributed to a subpopulation of cells called gliomastem cells (GSCs). To meet the present shortage of relevant GBM cell (GC) lines we developed a library of annotated and validated cell lines derived from surgical samples of GBM patients, maintained under conditions to preserve GSC characteristics. This collection, which we call the Human Glioblastoma Cell Culture (HGCC) resource, consists of a biobank of 48 GC lines and an associated database containing high-resolution molecular data. We demonstrate that the HGCC lines are tumorigenic, harbor genomic lesions characteristic of GBMs, and represent all four transcriptional sub-types. The HGCC panel provides an open resource for in vitro and in vivo modeling of a large part of GBM diversity useful to both basic and translational GBM research.

    Emneord
    Glioblastoma, Cell culture, Stem cell culture condition, Molecular subtype, Xenograft models
    HSV kategori
    Forskningsprogram
    Patologi; Patologi
    Identifikatorer
    urn:nbn:se:uu:diva-274354 (URN)10.1016/j.ebiom.2015.08.026 (DOI)000365959700034 ()26629530 (PubMedID)
    Merknad

    De två sista författarna delar sistaförfattarskapet.

    Tilgjengelig fra: 2016-01-21 Laget: 2016-01-21 Sist oppdatert: 2019-04-02bibliografisk kontrollert
    3. Decoding glioblastoma drug responses using an open access library of patient derived cell models
    Åpne denne publikasjonen i ny fane eller vindu >>Decoding glioblastoma drug responses using an open access library of patient derived cell models
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    Emneord
    glioblastoma, GBM, precision medicine, drug response predictions, proteasome inhibitors, bortezomib
    HSV kategori
    Forskningsprogram
    Biologi med inriktning mot molekylärbiologi; Onkologi; Bioinformatik; Medicinsk vetenskap
    Identifikatorer
    urn:nbn:se:uu:diva-340308 (URN)
    Tilgjengelig fra: 2018-02-04 Laget: 2018-02-04 Sist oppdatert: 2018-02-04
    4. Exploring large scale integrative networks of glioblastoma using hypothesis driven pattern search
    Åpne denne publikasjonen i ny fane eller vindu >>Exploring large scale integrative networks of glioblastoma using hypothesis driven pattern search
    Vise andre…
    (engelsk)Manuskript (preprint) (Annet vitenskapelig)
    HSV kategori
    Identifikatorer
    urn:nbn:se:uu:diva-340341 (URN)
    Tilgjengelig fra: 2018-01-29 Laget: 2018-01-29 Sist oppdatert: 2018-02-04
  • 48.
    Johansson, Patrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Almstedt, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Doroszko, Milena
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Kundu, Soumi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Vinel, Claire
    Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
    Schmidt, Linnéa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Department of Molecular Medicine, Aarhus University, Aarhus, DK.
    Baskaran, Sathishkumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg. Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Gallant, Caroline
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Lundsten, Sara
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Rosén, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Elgendy, Ramy
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Elfineh, Ludmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Häggblad, Maria
    Department of Biochemistry and Biophysics, Stockholm University, BCS, SciLifeLab, SE.
    Martens, Ulf
    Department of Biochemistry and Biophysics, Stockholm University, BCS, SciLifeLab, SE.
    Lundgren, Bo
    Department of Biochemistry and Biophysics, Stockholm University, BCS, SciLifeLab, SE.
    Frigault, Melanie M.
    Translational Science, Acerta Pharmaceuticals, CA, US.
    Lane, David P.
    Dept of Microbiology, Tumor and Cell Biology, Karolinska Institutet, SE.
    Nestor, Marika
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Medicinsk strålningsvetenskap.
    Marino, Silvia
    Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK.
    Krona, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    A drug association map of glioblastoma informs precision targeting of p53-dependent metabolic statesInngår i: Artikkel i tidsskrift (Annet vitenskapelig)
  • 49.
    Johansson, Patrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Rosén, Emil
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Weishaupt, Holger
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Exploring large scale integrative networks of glioblastoma using hypothesis driven pattern searchManuskript (preprint) (Annet vitenskapelig)
  • 50.
    Johansson, Patrik
    et al.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Schmidt, Linnéa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Department of Molecular Medicine, Aarhus University, Aarhus, Denmark.
    Baskaran, Sathishkumar
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Kundu, Soumi
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Gallant, Caroline J.
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Molekylära verktyg.
    Kling, Teresia
    Sahlgrenska Cancer Center, Department of Pathology and Genetics, University of Gothenburg, Sweden.
    Awe, Olatilewa
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Department of Neurosurgery, University of Iowa, IA, USA.
    Elfineh, Lioudmila
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Holmberg Olausson, Karl
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Almstedt, Elin
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Häggblad, Maria
    Department of Biochemistry and Biophysics, Stockholm University, Sweden, BCS, SciLifeLab, Sweden.
    Martens, Ulf
    Department of Biochemistry and Biophysics, Stockholm University, Sweden, BCS, SciLifeLab, Sweden.
    Lundgren, Bo
    Department of Biochemistry and Biophysics, Stockholm University, Sweden, BCS, SciLifeLab, Sweden.
    Lönnstedt, Ingrid
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi. Walter and Eliza Hall Institute of Medical Research, Australia.
    Frigault, Melanie M.
    Translational Sciences, Oncology, IMED Biotech Unit, AstraZeneca, Boston, US.
    Hurt, Elaine
    Division of Oncology, Medimmune LLC, Gaithersburg, MD, USA.
    Jörnsten, Rebecka
    Mathematical Sciences, Chalmers University of Technology, Gothenburg, Sweden.
    Krona, Cecilia
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi.
    Nelander, Sven
    Uppsala universitet, Medicinska och farmaceutiska vetenskapsområdet, Medicinska fakulteten, Institutionen för immunologi, genetik och patologi, Neuroonkologi.
    Decoding glioblastoma drug responses using an open access library of patient derived cell modelsManuskript (preprint) (Annet vitenskapelig)
123 1 - 50 of 112
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