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Čančer, M., Hutter, S., Holmberg Olausson, K., Rosén, G., Sundström, A., Tailor, J., . . . Johansson, F. K. (2019). Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy. Cell Stem Cell, 25(6), 855-870
Åpne denne publikasjonen i ny fane eller vindu >>Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy
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2019 (engelsk)Inngår i: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 25, nr 6, s. 855-870Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Medulloblastoma (MB), the most frequent malignant childhood brain tumor, can arise from cellular malfunctions during hindbrain development. Here we generate humanized models for Sonic Hedgehog (SHH)-subgroup MB via MYCN overexpression in primary human hindbrain-derived neuroepithelial stem (hbNES) cells or iPSC-derived NES cells, which display a range of aggressive phenotypes upon xenografting. iPSC-derived NES tumors develop quickly with leptomeningeal dissemination, whereas hbNES-derived cells exhibit delayed tumor formation with less dissemination. Methylation and expression profiling show that tumors from both origins recapitulate hallmarks of infant SHH MB and reveal that mTOR activation, as a result of increased Oct4, promotes aggressiveness of human SHH tumors. Targeting mTOR decreases cell viability and prolongs survival, showing the utility of these varied models for dissecting mechanisms mediating tumor aggression and demonstrating the value of humanized models for a better understanding of pediatric cancers.

sted, utgiver, år, opplag, sider
CELL PRESS, 2019
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-400664 (URN)10.1016/j.stem.2019.10.005 (DOI)000500942400013 ()31786016 (PubMedID)
Forskningsfinansiär
EU, Horizon 2020, 640275Swedish Cancer SocietySwedish Research CouncilKnut and Alice Wallenberg FoundationSwedish Childhood Cancer FoundationScience for Life Laboratory - a national resource center for high-throughput molecular bioscienceRagnar Söderbergs stiftelse
Tilgjengelig fra: 2020-01-03 Laget: 2020-01-03 Sist oppdatert: 2020-01-03bibliografisk kontrollert
Xie, Y., Sundström, A., Maturi, N. P., Tan, E.-J., Marinescu, V. D., Jarvius, M., . . . Uhrbom, L. (2019). LGR5 promotes tumorigenicity and invasion of glioblastoma stem-like cells and is a potential therapeutic target for a subset of glioblastoma patients. Journal of Pathology, 247(2), 228-240
Åpne denne publikasjonen i ny fane eller vindu >>LGR5 promotes tumorigenicity and invasion of glioblastoma stem-like cells and is a potential therapeutic target for a subset of glioblastoma patients
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2019 (engelsk)Inngår i: Journal of Pathology, ISSN 0022-3417, E-ISSN 1096-9896, Vol. 247, nr 2, s. 228-240Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Glioblastoma (GBM) is the most common and lethal primary malignant brain tumor which lacks efficient treatment and predictive biomarkers. Expression of the epithelial stem cell marker Leucine-rich repeat-containing G-protein coupled receptor 5 (LGR5) has been described in GBM, but its functional role has not been conclusively elucidated. Here, we have investigated the role of LGR5 in a large repository of patient-derived GBM stem cell (GSC) cultures. The consequences of LGR5 overexpression or depletion have been analyzed using in vitro and in vivo methods, which showed that, among those with highest LGR5 expression (LGR5(high)), there were two phenotypically distinct groups: one that was dependent on LGR5 for its malignant properties and another that was unaffected by changes in LGR5 expression. The LGR5-responding cultures could be identified by their significantly higher self-renewal capacity as measured by extreme limiting dilution assay (ELDA), and these LGR5(high)-ELDA(high) cultures were also significantly more malignant and invasive compared to the LGR5(high)-ELDA(low) cultures. This showed that LGR5 expression alone would not be a strict marker of LGR5 responsiveness. In a search for additional biomarkers, we identified LPAR4, CCND2, and OLIG2 that were significantly upregulated in LGR5-responsive GSC cultures, and we found that OLIG2 together with LGR5 were predictive of GSC radiation and drug response. Overall, we show that LGR5 regulates the malignant phenotype in a subset of patient-derived GSC cultures, which supports its potential as a predictive GBM biomarker. Copyright (c) 2018 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

sted, utgiver, år, opplag, sider
John Wiley & Sons, 2019
Emneord
glioblastoma stem-like cells, LGR5, self-renewal, invasion, radiation response
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-376723 (URN)10.1002/path.5186 (DOI)000456331900009 ()30357839 (PubMedID)
Forskningsfinansiär
Swedish Research Council, 2012-02591Swedish Cancer Society, 2012/4882015/656
Tilgjengelig fra: 2019-02-11 Laget: 2019-02-11 Sist oppdatert: 2019-02-11bibliografisk kontrollert
Martikainen, M. & Essand, M. (2019). Virus-Based Immunotherapy of Glioblastoma. Cancers, 11(2), Article ID 186.
Åpne denne publikasjonen i ny fane eller vindu >>Virus-Based Immunotherapy of Glioblastoma
2019 (engelsk)Inngår i: Cancers, ISSN 2072-6694, Vol. 11, nr 2, artikkel-id 186Artikkel, forskningsoversikt (Fagfellevurdert) Published
Abstract [en]

Glioblastoma (GBM) is the most common type of primary brain tumor in adults. Despite recent advances in cancer therapy, including the breakthrough of immunotherapy, the prognosis of GBM patients remains dismal. One of the new promising ways to therapeutically tackle the immunosuppressive GBM microenvironment is the use of engineered viruses that kill tumor cells via direct oncolysis and via stimulation of antitumor immune responses. In this review, we focus on recently published results of phase I/II clinical trials with different oncolytic viruses and the new interesting findings in preclinical models. From syngeneic preclinical GBM models, it seems evident that oncolytic virus-mediated destruction of GBM tissue coupled with strong adjuvant effect, provided by the robust stimulation of innate antiviral immune responses and adaptive anti-tumor T cell responses, can be harnessed as potent immunotherapy against GBM. Although clinical testing of oncolytic viruses against GBM is at an early stage, the promising results from these trials give hope for the effective treatment of GBM in the near future.

Emneord
oncolytic virotherapy, cancer immunotherapy, glioblastoma
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-380671 (URN)10.3390/cancers11020186 (DOI)000460747200060 ()30764570 (PubMedID)
Forskningsfinansiär
Swedish Research Council, 2015-03688Swedish Childhood Cancer Foundation, PR2015-0049Swedish Cancer Society, CAN 2016/318
Tilgjengelig fra: 2019-04-01 Laget: 2019-04-01 Sist oppdatert: 2019-04-01bibliografisk kontrollert
Enblad, G., Karlsson, H., Gammelgård, G., Wenthe, J., Lövgren, T., Amini, R.-M., . . . Loskog, A. (2018). A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia. Clinical Cancer Research, 24(24), 6185-6194
Åpne denne publikasjonen i ny fane eller vindu >>A Phase I/IIa Trial Using CD19-Targeted Third-Generation CAR T Cells for Lymphoma and Leukemia
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2018 (engelsk)Inngår i: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 24, nr 24, s. 6185-6194Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Purpose: The chimeric antigen receptor (CAR) T-cell therapy has been effective for patients with CD19(+) B-cell malignancies. Most studies have investigated the second-generation CARs with either CD28 or 4-1BB costimulatory domains in the CAR receptor. Here, we describe the first clinical phase I/IIa trial using third-generation CAR T cells targeting CD19 to evaluate safety and efficacy.

Patients and Methods: Fifteen patients with B-cell lymphoma or leukemia were treated with CAR T cells. The patients with lymphoma received chemotherapy during CAR manufacture and 11 of 15 were given low-dose cyclophosphamide and fludarabine conditioning prior to CAR infusion. Peripheral blood was sampled before and at multiple time points after CAR infusion to evaluate the persistence of CAR T cells and for immune profiling, using quantitative PCR, flow cytometry, and a proteomic array.

Results: Treatment with third-generation CAR T cells was generally safe with 4 patients requiring hospitalization due to adverse reactions. Six of the 15 patients had initial complete responses [4/11 lymphoma and 2/4 acute lymphoblastic leukemia (ALL)], and 3 of the patients with lymphoma were in remission at 3 months. Two patients are still alive. Best predictor of response was a good immune status prior to CAR infusion with high IL12, DC-Lamp, Fas ligand, and TRAIL. Responding patients had low monocytic myeloid-derived suppressor cells (MDSCs; CD14(+)CD33(+)HLA(-)DR(-)) and low levels of IL6, IL8, NAP3, sPDL1, and sPDL2.

Conclusions: Third-generation CARs may be efficient in patients with advanced B-cell lymphoproliferative malignancy with only modest toxicity. Immune profiling pre- and posttreatment can be used to find response biomarkers.

HSV kategori
Forskningsprogram
Patologi
Identifikatorer
urn:nbn:se:uu:diva-372924 (URN)10.1158/1078-0432.CCR-18-0426 (DOI)000453267600012 ()30097433 (PubMedID)
Forskningsfinansiär
Swedish Research CouncilAFA InsuranceSwedish Cancer Society
Tilgjengelig fra: 2019-01-10 Laget: 2019-01-10 Sist oppdatert: 2019-03-29bibliografisk kontrollert
Fotaki, G., Jin, C., Kerzeli, I. K., Ramachandran, M., Martikainen, M.-M., Karlsson-Parra, A., . . . Essand, M. (2018). Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models. Oncoimmunology, 7(3), Article ID e1397250.
Åpne denne publikasjonen i ny fane eller vindu >>Cancer vaccine based on a combination of an infection-enhanced adenoviral vector and pro-inflammatory allogeneic DCs leads to sustained antigen-specific immune responses in three melanoma models
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2018 (engelsk)Inngår i: Oncoimmunology, ISSN 2162-4011, E-ISSN 2162-402X, Vol. 7, nr 3, artikkel-id e1397250Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Autologous patient-derived dendritic cells (DCs) modified ex vivo to present tumor-associated antigens (TAAs) are frequently used as cancer vaccines. However, apart from the stringent logistics in producing DCs on a patient basis, accumulating evidence indicate that ex vivo engineered DCs are poor in migration and in fact do not directly present TAA epitopes to naïve T cells in vivo. Instead, it is proposed that bystander host DCs take up material from vaccine-DCs, migrate and subsequently initiate antitumor T-cell responses. We used mouse models to examine the possibility of using pro-inflammatory allogeneic DCs (alloDCs) to activate host DCs and enable them to promote antigen-specific T-cell immunity. We found that alloDCs were able to initiate host DC activation and migration to draining lymph node leading to T-cell activation. The pro-inflammatory milieu created by alloDCs also led to recruitment of NK cells and neutrophils at the site of injection. Vaccination with alloDCs combined with Ad5M(gp100), an infection-enhanced adenovirus encoding the human melanoma-associated antigen gp100 resulted in generation of CD8+ T cells with a T-cell receptor (TCR) specific for the gp10025-33 epitope (gp100-TCR+). Ad5M(gp100)-alloDC vaccination in combination with transfer of gp100-specific pmel-1 T cells resulted in prolonged survival of B16-F10 melanoma-bearing mice and altered the composition of the tumor microenvironment (TME). We hereby propose that alloDCs together with TAA- or neoepitope-encoding Ad5M can become an “off-the-shelf” cancer vaccine, which can reverse the TME-induced immunosuppression and induce host cellular anti-tumor immune responses in patients without the need of a time-consuming preparation step of autologous DCs.

Emneord
adjuvants, Allogeneic dendritic cells, cell-based immunotherapy, tumor microenvironment, tumor-associated antigen
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-346362 (URN)10.1080/2162402X.2017.1397250 (DOI)000423567000013 ()29399398 (PubMedID)
Forskningsfinansiär
Swedish Cancer Society, CAN 2013/373; CAN 2016/318Swedish Childhood Cancer Foundation, PR2015-0049Swedish Research Council, 2015-03688
Tilgjengelig fra: 2018-03-16 Laget: 2018-03-16 Sist oppdatert: 2019-02-21bibliografisk kontrollert
Lugano, R., Vemuri, K., Yu, D., Bergqvist, M., Smits, A., Essand, M., . . . Dimberg, A. (2018). CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.. Journal of Clinical Investigation, 128(8), 3280-3297
Åpne denne publikasjonen i ny fane eller vindu >>CD93 promotes β1 integrin activation and fibronectin fibrillogenesis during tumor angiogenesis.
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2018 (engelsk)Inngår i: Journal of Clinical Investigation, ISSN 0021-9738, E-ISSN 1558-8238, Vol. 128, nr 8, s. 3280-3297Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

Tumor angiogenesis occurs through regulation of genes that orchestrate endothelial sprouting and vessel maturation, including deposition of a vessel-associated extracellular matrix. CD93 is a transmembrane receptor that is up-regulated in tumor vessels in many cancers, including high-grade glioma. Here, we demonstrate that CD93 regulates integrin-β1-signaling and organization of fibronectin fibrillogenesis during tumor vascularization. In endothelial cells and mouse retina, CD93 was found to be expressed in endothelial filopodia and to promote filopodia formation. The CD93 localization to endothelial filopodia was stabilized by interaction with multimerin-2 (MMRN2), which inhibited its proteolytical cleavage. The CD93-MMRN2 complex was required for activation of integrin-β1, phosphorylation of focal adhesion kinase (FAK) and fibronectin fibrillogenesis in endothelial cells. Consequently, tumor vessels in gliomas implanted orthotopically in CD93-deficient mice showed diminished activation of integrin-β1 and lacked organization of fibronectin into fibrillar structures. These findings demonstrate a key role of CD93 in vascular maturation and organization of the extracellular matrix in tumors, identifying it as a potential target for therapy.

Emneord
Brain cancer, Fibronectin, Oncology, Vascular Biology, endothelial cells
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-350902 (URN)10.1172/JCI97459 (DOI)000440461500015 ()29763414 (PubMedID)
Forskningsfinansiär
Swedish Cancer Society, CAN 2014/832Swedish Cancer Society, CAN 2017/502Swedish Cancer Society, CAN 2015/1216Swedish Childhood Cancer Foundation, PR2015-0133Swedish Childhood Cancer Foundation, NCP2015-0075Swedish Research Council, 2016-02495
Tilgjengelig fra: 2018-05-17 Laget: 2018-05-17 Sist oppdatert: 2018-11-08bibliografisk kontrollert
Roche, F. P., Pietilä, I., Kaito, H., Sjöström, E. O., Sobotzki, N., Noguer, O., . . . Claesson-Welsh, L. (2018). Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity. Molecular Cancer Therapeutics, 17(9), 1961-1972
Åpne denne publikasjonen i ny fane eller vindu >>Leukocyte differentiation by histidine-rich glycoprotein/stanniocalcin-2 complex regulates murine glioma growth through modulation of anti-tumor immunity
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2018 (engelsk)Inngår i: Molecular Cancer Therapeutics, ISSN 1535-7163, E-ISSN 1538-8514, Vol. 17, nr 9, s. 1961-1972Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The plasma-protein histidine-rich glycoprotein (HRG) is implicated in phenotypic switching of tumor-associated macrophages, regulating cytokine production and phagocytotic activity, thereby promoting vessel normalization and anti-tumor immune responses. To assess the therapeutic effect of HRG gene delivery on CNS tumors, we used adenovirus-encoded HRG to treat mouse intracranial GL261 glioma. Delivery of Ad5-HRG to the tumor site resulted in a significant reduction in glioma growth, associated with increased vessel perfusion and increased CD45+ leukocyte and CD8+ T cell accumulation in the tumor. Antibody-mediated neutralization of colony-stimulating factor-1 suppressed the effects of HRG on CD45+ and CD8+ infiltration. Using a novel protein interaction-decoding technology, TRICEPS-based ligand receptor capture (LRC), we identified Stanniocalcin-2 (STC2) as an interacting partner of HRG on the surface of inflammatory cells in vitro and co-localization of HRG and STC2 in gliomas. HRG reduced the suppressive effects of STC2 on monocyte CD14+ differentiation and STC2-regulated immune response pathways. In consequence, Ad5-HRG treated gliomas displayed decreased numbers of Interleukin-35+ Treg cells, providing a mechanistic rationale for the reduction in GL261 growth in response to Ad5-HRG delivery. We conclude that HRG suppresses glioma growth by modulating tumor inflammation through monocyte infiltration and differentiation. Moreover, HRG acts to balance the regulatory effects of its partner, STC2, on inflammation and innate and/or acquired immunity. HRG gene delivery therefore offers a potential therapeutic strategy to control anti-tumor immunity.

HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-356836 (URN)10.1158/1535-7163.MCT-18-0097 (DOI)000444041300015 ()29945872 (PubMedID)
Forskningsfinansiär
Swedish Cancer Society, 16 0585Swedish Cancer Society, 16 0520Swedish Research Council, 2015-02375_3Swedish Research Council, 2016-01085
Merknad

I. Pietilä and H. Kaito contributed equally to this article.

Tilgjengelig fra: 2018-08-08 Laget: 2018-08-08 Sist oppdatert: 2018-11-26bibliografisk kontrollert
Shridhar, N., Ruotsalainen, J., van der Sluis, T., Rogava, M., Yu, D., Essand, M., . . . Tueting, T. (2018). Modifying melanoma immune microenvironment by heterologous prime-boost vaccination with adenovirus and Modified Vaccinia Ankara virus vectors. Paper presented at 45th Annual Meeting of the Arbeitsgemeinscha-Dermatologische-Forschung (ADF), MAR 07-10, 2018, Zurich, SWITZERLAND. Experimental dermatology, 27(3), E54-E55
Åpne denne publikasjonen i ny fane eller vindu >>Modifying melanoma immune microenvironment by heterologous prime-boost vaccination with adenovirus and Modified Vaccinia Ankara virus vectors
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2018 (engelsk)Inngår i: Experimental dermatology, ISSN 0906-6705, E-ISSN 1600-0625, Vol. 27, nr 3, s. E54-E55Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-361438 (URN)000427009500127 ()
Konferanse
45th Annual Meeting of the Arbeitsgemeinscha-Dermatologische-Forschung (ADF), MAR 07-10, 2018, Zurich, SWITZERLAND
Tilgjengelig fra: 2018-12-10 Laget: 2018-12-10 Sist oppdatert: 2019-02-07bibliografisk kontrollert
Younis, S., Kamel, W., Falkeborn, T., Wang, H., Yu, D., Daniels, R., . . . Andersson, L. (2018). Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth. Proceedings of the National Academy of Sciences of the United States of America, 115(16), E3808-E3816
Åpne denne publikasjonen i ny fane eller vindu >>Multiple nuclear-replicating viruses require the stress-induced protein ZC3H11A for efficient growth
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2018 (engelsk)Inngår i: Proceedings of the National Academy of Sciences of the United States of America, ISSN 0027-8424, E-ISSN 1091-6490, Vol. 115, nr 16, s. E3808-E3816Artikkel i tidsskrift (Fagfellevurdert) Published
Abstract [en]

The zinc finger CCCH-type containing 11A (ZC3H11A) gene encodes a well-conserved zinc finger protein that may function in mRNA export as it has been shown to associate with the transcription export (TREX) complex in proteomic screens. Here, we report that ZC3H11A is a stress-induced nuclear protein with RNA-binding capacity that localizes to nuclear splicing speckles. During an adenovirus infection, the ZC3H11A protein and splicing factor SRSF2 relocalize to nuclear regions where viral DNA replication and transcription take place. Knockout (KO) of ZC3H11A in HeLa cells demonstrated that several nuclear-replicating viruses are dependent on ZC3H11A for efficient growth (HIV, influenza virus, herpes simplex virus, and adenovirus), whereas cytoplasmic replicating viruses are not (vaccinia virus and Semliki Forest virus). High-throughput sequencing of ZC3H11A-cross-linked RNA showed that ZC3H11A binds to short purine-rich ribonucleotide stretches in cellular and adenoviral transcripts. We show that the RNA-binding property of ZC3H11A is crucial for its function and localization. In ZC3H11A KO cells, the adenovirus fiber mRNA accumulates in the cell nucleus. Our results suggest that ZC3H11A is important for maintaining nuclear export of mRNAs during stress and that several nuclear-replicating viruses take advantage of this mechanism to facilitate their replication.

Emneord
ZC3H11A, mRNA export, stress response, virus infection
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-354118 (URN)10.1073/pnas.1722333115 (DOI)000430191900026 ()29610341 (PubMedID)
Forskningsfinansiär
Knut and Alice Wallenberg Foundation
Merknad

De 2 första författarna delar förstaförfattarskapet.

Tilgjengelig fra: 2018-06-19 Laget: 2018-06-19 Sist oppdatert: 2018-06-19bibliografisk kontrollert
Vågesjö, E., Seignez, C., Christoffersson, G., Herrera Hidalgo, C., Giraud, A., Korsgren, O., . . . Phillipson, M. (2018). Perivascular macrophages regulate blood flow following tissue damage. Paper presented at 52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.. European Journal of Clinical Investigation, 48(S1), 44-45
Åpne denne publikasjonen i ny fane eller vindu >>Perivascular macrophages regulate blood flow following tissue damage
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2018 (engelsk)Inngår i: European Journal of Clinical Investigation, ISSN 0014-2972, E-ISSN 1365-2362, Vol. 48, nr S1, s. 44-45Artikkel i tidsskrift, Meeting abstract (Annet vitenskapelig) Published
HSV kategori
Identifikatorer
urn:nbn:se:uu:diva-366622 (URN)10.1111/eci.12923 (DOI)000434100200105 ()
Konferanse
52nd Annual Scientific Meeting of the European Society for Clinical Investigation “Precision medicine for healthy ageing”, 30th May – 1st June 2018, Barcelona, Spain.
Merknad

Meeting Abstract: W1-O2

Tilgjengelig fra: 2018-11-23 Laget: 2018-11-23 Sist oppdatert: 2018-12-10bibliografisk kontrollert
Organisasjoner
Identifikatorer
ORCID-id: ORCID iD iconorcid.org/0000-0002-9725-0422