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Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
Univ Cambridge, MRC Stem Cell Inst, Wellcome Trust, Tennis Court Rd, Cambridge CB2 1QR, England;Inst Canc Res, London SM2 5NG, England;Hosp Sick Children, Dev & Stem Cell Biol Program, Toronto, ON, Canada;Hosp Sick Children, Div Neurosurg, Toronto, ON, Canada.
Univ Calif San Francisco, Dept Neurol, San Francisco, CA 94158 USA;Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94158 USA.
Univ Calgary, Dept Biochem & Mol Biol, Calgary, AB, Canada;Univ Calgary, Charbonneau Canc Inst, Calgary, AB, Canada;Alberta Childrens Prov Gen Hosp, Res Inst, Calgary, AB, Canada.
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2019 (English)In: Cell Stem Cell, ISSN 1934-5909, E-ISSN 1875-9777, Vol. 25, no 3, p. 433-+Article in journal (Refereed) Published
Abstract [en]

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

Place, publisher, year, edition, pages
CELL PRESS , 2019. Vol. 25, no 3, p. 433-+
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Cell and Molecular Biology Cell Biology
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URN: urn:nbn:se:uu:diva-394687DOI: 10.1016/j.stem.2019.05.013ISI: 000484603600014PubMedID: 31204176OAI: oai:DiVA.org:uu-394687DiVA, id: diva2:1365321
Available from: 2019-10-24 Created: 2019-10-24 Last updated: 2019-10-24Bibliographically approved

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Weishaupt, HolgerChavez, LukasKoch, PhilippJohansson Swartling, FredrikTaylor, Michael D.Weiss, William A.
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