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Humanized Stem Cell Models of Pediatric Medulloblastoma Reveal an Oct4/mTOR Axis that Promotes Malignancy
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, Science for Life Laboratory, SciLifeLab. 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, Neuro-Oncology. Uppsala University, Science for Life Laboratory, SciLifeLab.
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.
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2019 (English)In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 25, no 6, p. 855-870Article in journal (Refereed) 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.

Place, publisher, year, edition, pages
CELL PRESS , 2019. Vol. 25, no 6, p. 855-870
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Cell Biology Cell and Molecular Biology
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URN: urn:nbn:se:uu:diva-400664DOI: 10.1016/j.stem.2019.10.005ISI: 000500942400013PubMedID: 31786016OAI: oai:DiVA.org:uu-400664DiVA, id: diva2:1382429
Funder
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 stiftelseAvailable from: 2020-01-03 Created: 2020-01-03 Last updated: 2020-01-03Bibliographically approved

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Čančer, MatkoHutter, SonjaHolmberg Olausson, KarlRosén, GabrielaSundström, AndersBergström, TobiasEssand, MagnusWeishaupt, HolgerJohansson, Fredrik K.
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