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  • 1.
    Agarwal, Prasoon
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Collier, Paul
    Fritz, Markus Hsi-Yang
    Benes, Vladimir
    Wiklund, Helena Jernberg
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Singh, Umashankar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    CGGBP1 mitigates cytosine methylation at repetitive DNA sequences2015In: BMC Genomics, ISSN 1471-2164, E-ISSN 1471-2164, Vol. 16, article id 390Article in journal (Refereed)
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Bjerke, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Karolinska Inst, Dept Lab Med, SE-14186 Stockholm, Sweden..
    Edlund, Hanna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Science and Technology, Biology, Department of Organismal Biology, Evolution and Developmental Biology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Origin of the U87MG glioma cell line: Good news and bad news2016In: Science Translational Medicine, ISSN 1946-6234, E-ISSN 1946-6242, Vol. 8, no 354, article id 354re3Article in journal (Refereed)
    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.
    Arvidsson, Per I.
    et al.
    Uppsala University, 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 University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Pharmacy, Department of Medicinal Chemistry, Organic Pharmaceutical Chemistry. Department of Physiology and Pharmacology, Karolinska Institutet, Stockholm, Sweden.
    Forsberg-Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Open for collaboration: an academic platform for drug discovery and development at SciLifeLab2016In: Drug Discovery Today, ISSN 1359-6446, E-ISSN 1878-5832, Vol. 21, no 10, p. 1690-1698Article, review/survey (Refereed)
    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.

  • 4. Attarha, Sanaz
    et al.
    Roy, Ananya
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Swedish Univ Agr Sci, Dept Biomed Sci & Vet Publ Hlth, Box 7028, SE-75007 Uppsala, Sweden..
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mast cells modulate proliferation, migration and sternness of glioma cells through downregulation of GSK3 beta expression and inhibition of STAT3 activation2017In: Cellular Signalling, ISSN 0898-6568, E-ISSN 1873-3913, Vol. 37, p. 81-92Article in journal (Refereed)
    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.

  • 5.
    Babateen, Omar M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Jin, Zhe
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Bhandage, Amol K.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Korol, Sergiy V.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Physiology.
    Westermark, Bengt
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nilsson, Karin Forsberg
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Smits, Anja
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    Birnir, Bryndis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurology.
    GABA-A receptor currents in a cell line (U3047MG) derived from a human glioblastoma tumor are enhanced by etomidate, propofol and diazepam2014In: Acta Physiologica, ISSN 1748-1708, E-ISSN 1748-1716, Vol. 211, no S696, p. 100-100, article id P74Article in journal (Other academic)
  • 6.
    Baskaran, Sathishkumar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Department of IGP, Uppsala University.
    New Molecular Approaches to Glioblastoma Therapy2017Doctoral thesis, comprehensive summary (Other academic)
    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. 

    List of papers
    1. Case-specific potentiation of glioblastoma drugs by pterostilbene
    Open this publication in new window or tab >>Case-specific potentiation of glioblastoma drugs by pterostilbene
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    2016 (English)In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 7, no 45, p. 73200-73215Article in journal (Refereed) Published
    National Category
    Cancer and Oncology Medical Genetics
    Identifiers
    urn:nbn:se:uu:diva-309806 (URN)10.18632/oncotarget.12298 (DOI)000387452100060 ()
    Funder
    Swedish Research CouncilSwedish Cancer SocietySwedish Childhood Cancer Foundation
    Available from: 2016-09-28 Created: 2016-12-07 Last updated: 2018-01-13Bibliographically approved
    2. Targeting tumor heterogeneity: multi-omic modeling of glioblastoma drug response using an open-access library of patient-derived cells
    Open this publication in new window or tab >>Targeting tumor heterogeneity: multi-omic modeling of glioblastoma drug response using an open-access library of patient-derived cells
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    GBM, Proteasome inhibitors, Precision medicine, Bortezomib, drug predictions
    National Category
    Cancer and Oncology Cell and Molecular Biology Medical Biotechnology (with a focus on Cell Biology (including Stem Cell Biology), Molecular Biology, Microbiology, Biochemistry or Biopharmacy)
    Research subject
    Biology with specialization in Molecular Biology; Oncology; Bioinformatics; Medical Science
    Identifiers
    urn:nbn:se:uu:diva-329756 (URN)
    Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2018-01-13
    3. Loss of transcription factor ZBTB16 induces cell death in patient-derived GBM cell lines
    Open this publication in new window or tab >>Loss of transcription factor ZBTB16 induces cell death in patient-derived GBM cell lines
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    PLZF, ZBTB16, GBM, Glioblastoma
    National Category
    Cancer and Oncology Cell and Molecular Biology
    Research subject
    Biology with specialization in Molecular Cell Biology; Oncology
    Identifiers
    urn:nbn:se:uu:diva-329752 (URN)
    Available from: 2017-09-20 Created: 2017-09-20 Last updated: 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
    Open this publication in new window or tab >>Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages: glioblastoma cells for precision medicine
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    Patient derived GBM cell cultures, Systems biology, Subclones, Glioma stem cell cultures, GBM subtype
    National Category
    Cancer and Oncology
    Research subject
    Oncology; Biology; Medical Science
    Identifiers
    urn:nbn:se:uu:diva-329742 (URN)
    Available from: 2017-09-20 Created: 2017-09-20 Last updated: 2017-10-22
  • 7.
    Baskaran, Sathishkumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Department of IGP, Uppsala University.
    Johansson, Patrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Hansson, Caroline
    Sahlgrenska Cancer Center, University of Gothenburg.
    Spyrou, Argyris
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Kalushkova, Antonia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Ramachandran, Mohanraj
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Atienza Párraga, Alba
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Nordling, Torbjörn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Martens, Ulf
    Cell screening facility, Science for Life Laboratory Stockholm.
    Häggblad, Maria
    Cell screening facility, Science for Life Laboratory Stockholm.
    Kundu, Soumi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Forsberg Nilsson, Karin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Lundgren, Bo
    Cell screening facility, Science for Life Laboratory Stockholm.
    Krona, Cecilia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Loss of transcription factor ZBTB16 induces cell death in patient-derived GBM cell linesManuscript (preprint) (Other academic)
  • 8.
    Baskaran, Sathishkumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Göransson Kultima, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Bergström, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Medicinsk genetik och genomik.
    Isaksson, Anders
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Cancer Pharmacology and Computational Medicine.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages2018In: Neuro-Oncology, ISSN 1522-8517, E-ISSN 1523-5866, Vol. 20, no 8, p. 1080-1091Article in journal (Refereed)
    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.

  • 9.
    Baskaran, Sathishkumar
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Department of IGP, Uppsala University.
    Mayrhofer, Markus
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Kultima, Hanna
    Uppsala University, Science for Life Laboratory, SciLifeLab.
    Elfineh, Lioudmila
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Cavelier, Lucia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Isaksson, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Primary glioblastoma cells for precision medicine: a quantitative portrait of genomic (in)stability during the first 30 passages: glioblastoma cells for precision medicineManuscript (preprint) (Other academic)
  • 10.
    Bolin, Sara
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Mechanisms of Medulloblastoma Dissemination and Novel Targeted Therapies2016Doctoral thesis, comprehensive summary (Other academic)
    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.

    List of papers
    1. FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
    Open this publication in new window or tab >>FBW7 suppression leads to SOX9 stabilization and increased malignancy in medulloblastoma
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    2016 (English)In: EMBO Journal, ISSN 0261-4189, E-ISSN 1460-2075, Vol. 35, no 20, p. 2192-2212Article in journal (Refereed) 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.

    Keywords
    FBW7, SOX9, Medulloblastoma, FBXW7, ubiquitin, migration, metastasis, drug resistance
    National Category
    Cell and Molecular Biology
    Identifiers
    urn:nbn:se:uu:diva-274626 (URN)10.15252/embj.201693889 (DOI)000385708000004 ()
    Funder
    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
    Note

    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

    Available from: 2016-01-24 Created: 2016-01-24 Last updated: 2018-01-10Bibliographically approved
    2. Metastasis and tumor recurrence from rare SOX9-positive cells in MYCN-driven medulloblastoma
    Open this publication in new window or tab >>Metastasis and tumor recurrence from rare SOX9-positive cells in MYCN-driven medulloblastoma
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    (English)Manuscript (preprint) (Other academic)
    Keywords
    SOX9, medulloblastoma, relapse, recurrence, MYCN, mouse model, pediatric cancer
    National Category
    Cell and Molecular Biology Cancer and Oncology Pediatrics
    Identifiers
    urn:nbn:se:uu:diva-274629 (URN)
    Available from: 2016-01-24 Created: 2016-01-24 Last updated: 2018-01-10
    3. BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
    Open this publication in new window or tab >>BET Bromodomain Inhibition of MYC-Amplified Medulloblastoma
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    2014 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 20, no 4, p. 912-925Article in journal (Refereed) 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.

    Keywords
    medulloblastoma, MYC
    National Category
    Cancer and Oncology
    Research subject
    Oncology
    Identifiers
    urn:nbn:se:uu:diva-217950 (URN)10.1158/1078-0432.CCR-13-2281 (DOI)000331875500015 ()
    Available from: 2014-02-06 Created: 2014-02-06 Last updated: 2017-12-06Bibliographically approved
    4. Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
    Open this publication in new window or tab >>Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastoma
    Show others...
    (English)Article in journal (Other academic) Submitted
    Keywords
    MYC, BET Bromodomains, Cyclin dependent kinases, Treatment, Medulloblastoma
    National Category
    Medical and Health Sciences
    Identifiers
    urn:nbn:se:uu:diva-300906 (URN)
    Available from: 2016-08-15 Created: 2016-08-15 Last updated: 2016-10-11
  • 11.
    Bolin, Sara
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Borgenvik, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Persson, Camilla U
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Sundström, Anders
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Qi, Jun
    Bradner, James E
    Cho, Yoon-Jae
    Weishaupt, Holger
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Swartling, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Combined BET-bromodomain and CDK2 inhibition in MYC-driven medulloblastomaArticle in journal (Other academic)
  • 12.
    Bolin, Sara M.
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Lau, Jasmine
    Chen, Justin
    Savov, Vasil
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Persson, Anders I.
    Hede, Sanna-Maria
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weiss, William A.
    Swartling, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Glial origin for MYCN-driven medulloblastoma and targeted prosenescence therapies2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 13.
    Caja, Laia
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Tzavlaki, Kalliopi
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Dadras, Mahsa Shahidi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Tan, E-Jean
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Hatem, Gad
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Maturi, Naga Prathyusha
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Morén, Anita
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Wik, Lotta
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Watanabe, Yukihide
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Univ Tsukuba, Dept Expt Pathol, Fac Med, Tsukuba, Ibaraki, Japan.
    Savary, Katia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research. Uppsala University, Science for Life Laboratory, SciLifeLab. Univ Reims, UMR CNRS MEDyC 7369, Reims, France.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhrbom, Lene
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Heldin, Carl-Henrik
    Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, Ludwig Institute for Cancer Research.
    Moustakas, Aristidis
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Snail regulates BMP and TGF beta pathways to control the differentiation status of glioma-initiating cells2018In: Oncogene, ISSN 0950-9232, E-ISSN 1476-5594, Vol. 37, no 19, p. 2515-2531Article in journal (Refereed)
    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.

  • 14.
    Cane, Gaëlle
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Leuchowius, Karl-Johan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Söderberg, Ola
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Kamali-Moghaddam, Masood
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Jarvis, Malin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Helbring, Irene
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Pardell, Katerina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Ebai, Tonge
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Koos, Björn
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Protein Diagnostics by Proximity Ligation: Combining Multiple Recognition and DNA Amplification for Improved Protein Analyses2017In: Molecular Diagnostics (Third Edition), 2016: Academia Press, 2017, 3, p. 219-231Chapter in book (Refereed)
    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.

  • 15.
    Darmanis, Spyros
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Gallant, Caroline Julie
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Marinescu, Voichita Dana
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Niklasson, Mia
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Segerman, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Flamourakis, Georgios
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Landegren, Ulf
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Molecular tools.
    Simultaneous Multiplexed Measurement of RNA and Proteins in Single Cells2016In: Cell reports, ISSN 2211-1247, E-ISSN 2211-1247, Vol. 14, no 2, p. 380-389Article in journal (Refereed)
    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.

  • 16.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Uhlen, Mathias
    KTH Royal Inst Technol, Sci Life Lab, SE-17121 Stockholm, Sweden..
    Ponten, Frederik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology. Uppsala University, 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/monocytes2015In: Experimental Cell Research, ISSN 0014-4827, E-ISSN 1090-2422, Vol. 339, no 2, p. 280-288Article in journal (Refereed)
    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.

  • 17.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    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 inhibitio2018In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, no 5, p. 1300-1319Article in journal (Refereed)
    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.

  • 18. Galli, Stephen J
    et al.
    Tsai, Mindy
    Marichal, Thomas
    Tchougounova, Elena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Reber, Laurent L
    Pejler, Gunnar
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Biochemistry and Microbiology.
    Approaches for analyzing the roles of mast cells and their proteases in vivo2015In: Advances in Immunology, ISSN 0065-2776, E-ISSN 1557-8445, Vol. 126, p. 45-127Article in journal (Refereed)
    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.

  • 19.
    Glimelius, Bengt
    et al.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Melin, Beatrice
    Umeå Univ, Dept Radiat Sci, Umeå.
    Enblad, Gunilla
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Alafuzoff, Irina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Beskow, Anna H.
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Medicinska och farmaceutiska vetenskapsområdet, centrumbildningar mm, UCR-Uppsala Clinical Research Center.
    Ahlström, Håkan
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Radiology.
    Bill-Axelson, Anna
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Birgisson, Helgi
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Upper Abdominal Surgery.
    Björ, Ove
    Umeå Univ, Dept Radiat Sci, Umeå.
    Edqvist, Per-Henrik D
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Hansson, Tony
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Helleday, Thomas
    Karolinska Inst, Div Translat Med & Chem Biol, Dept Med Biochem & Biophys, Sci Life Lab, Stockholm.
    Hellman, Per
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Henriksson, Kerstin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology.
    Hesselager, Göran
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Neuroscience, Neurosurgery.
    Hultdin, Magnus
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Häggman, Michael
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Urology.
    Höglund, Martin
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences, Haematology.
    Jonsson, Håkan
    Umeå Univ, Dept Radiat Sci, Umeå.
    Larsson, Chatarina
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Lindman, Henrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ljuslinder, Ingrid
    Umeå Univ, Dept Radiat Sci, Umeå.
    Mindus, Stephanie
    Akad Sjukhuset, Lung & Allergy Clin, Uppsala.
    Nygren, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    Ponten, Fredrik
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Riklund, Katrine
    Umeå Univ, Dept Radiat Sci, Umeå.
    Rosenquist, Richard
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Women's and Children's Health.
    Stålberg, Peter
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Surgical Sciences, Endocrine Surgery.
    Sundström, Christer
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Clinical and experimental pathology.
    Thellenberg Karlsson, Camilla
    Umeå Univ, Dept Radiat Sci, Umeå.
    Westermark, Bengt
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Bergh, Anders
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Claesson-Welsh, Lena
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Vascular Biology.
    Palmqvist, Richard
    Umeå Univ, Dept Med Biosci, Pathol, Umeå.
    Sjöblom, Tobias
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Experimental and Clinical Oncology.
    U-CAN: a prospective longitudinal collection of biomaterials and clinical information from adult cancer patients in Sweden.2018In: Acta Oncologica, ISSN 0284-186X, E-ISSN 1651-226X, Vol. 57, no 2, p. 187-194Article in journal (Refereed)
    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.

  • 20.
    Goroshchuk, Oksana
    et al.
    Karolinska Inst, S-10401 Stockholm, Sweden..
    Attarha, Sanaz
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    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 cancer2016In: Gynecological Endocrinology, ISSN 0951-3590, E-ISSN 1473-0766, Vol. 32, p. 117-117Article in journal (Other academic)
  • 21.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
    Nelander, Sven
    Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. Uppsala University, 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 gliomas2017In: OncoTarget, ISSN 1949-2553, E-ISSN 1949-2553, Vol. 8, no 4, p. 6940-6954Article in journal (Refereed)
    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.

  • 22. 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    Weiss, William A.
    Chesler, Louis
    Clifford, Steven C.
    Combined MYC and P53 Defects Emerge at Medulloblastoma Relapse and Define Rapidly Progressive, Therapeutically Targetable Disease2015In: Cancer Cell, ISSN 1535-6108, E-ISSN 1878-3686, Vol. 27, no 1, p. 72-84Article in journal (Refereed)
    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.

  • 23. 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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology.
    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 therapeutically2014In: Cancer Research, ISSN 0008-5472, E-ISSN 1538-7445, Vol. 74, no 19Article in journal (Other academic)
  • 24.
    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 University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Immunology, Genetics and Pathology, Neuro-Oncology. 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 Cons