Abstract
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 predisposed 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.
Original language | English (US) |
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Pages (from-to) | 433-446.e7 |
Journal | Cell Stem Cell |
Volume | 25 |
Issue number | 3 |
DOIs | |
State | Published - Sep 5 2019 |
Bibliographical note
Funding Information:We would like to thank Noemi Fusaki for the Sendai virus vectors. This study was supported in part by the HDFCCC Laboratory for Cell Analysis Shared Resource Facility through NIH grant P30CA082103 . M.H. was supported by a postdoctoral fellowship ( PF-13-295-01–TBG ) from the American Cancer Society , an Alex’s Lemonade Stand Foundation Young Investigator Award, a Family Support Award from the Research Evaluation & Allocation Committee at UCSF, and a K99 Pathway to Independence Award from the NIH NCI ( K99CA197484 ). J.T. was supported by a clinical research fellowship from the National Institute of Health Research (United Kingdom) and a postdoctoral research training fellowship from the Wellcome Trust (United Kingdom). T.M. was supported by the French Government (National Research Agency [ANR]; CNRS ; INSERM ) through the Investments for the Future LABEX SIGNALIFE (program reference ANR-11-LABX-0028-01 ), the UNS (Université de Nice Sophia Antipolis) and Association René Tourraine , Fondation ARC ( SFI201212055859 ), the Fondation de l'Avenir , the Société Française de Dermatologie , and the Institut National Du Cancer . P.K. was supported by the Hector Stiftung II gGmbH . Histopathologic processing and analysis were supported in part by the Pediatric Brain Tumor Foundation and UCSF Brain Tumor SPORE ( P50 CA097257 to J.J.P.). A.S. is a Medical Research Council Professor and is supported by the Medical Research Council of the United Kingdom ( G1001028 ). W.A.W. and M.D.T. were supported by a grant from the V Foundation ( T2017-020 ) and by R01CA159859 and R01NS106155 . W.A.W. was supported by the NIH grants R01NS089868 , U01CA217864 , and P30CA82103 ; Brain Tumour Charity grant GN356 ; the Evelyn and Mattie Anderson Chair ; the Ross K. MacNeill Foundation ; the Pediatric Brain Tumor Foundation ; the V Foundation ; and the Samuel G. Waxman Foundation .
Funding Information:
We would like to thank Noemi Fusaki for the Sendai virus vectors. This study was supported in part by the HDFCCC Laboratory for Cell Analysis Shared Resource Facility through NIH grant P30CA082103. M.H. was supported by a postdoctoral fellowship (PF-13-295-01–TBG) from the American Cancer Society, an Alex's Lemonade Stand Foundation Young Investigator Award, a Family Support Award from the Research Evaluation & Allocation Committee at UCSF, and a K99 Pathway to Independence Award from the NIH NCI (K99CA197484). J.T. was supported by a clinical research fellowship from the National Institute of Health Research (United Kingdom) and a postdoctoral research training fellowship from the Wellcome Trust (United Kingdom). T.M. was supported by the French Government (National Research Agency [ANR]; CNRS; INSERM) through the Investments for the Future LABEX SIGNALIFE (program reference ANR-11-LABX-0028-01), the UNS (Université de Nice Sophia Antipolis) and Association René Tourraine, Fondation ARC (SFI201212055859), the Fondation de l'Avenir, the Société Française de Dermatologie, and the Institut National Du Cancer. P.K. was supported by the Hector Stiftung II gGmbH. Histopathologic processing and analysis were supported in part by the Pediatric Brain Tumor Foundation and UCSF Brain Tumor SPORE (P50 CA097257 to J.J.P.). A.S. is a Medical Research Council Professor and is supported by the Medical Research Council of the United Kingdom (G1001028). W.A.W. and M.D.T. were supported by a grant from the V Foundation (T2017-020) and by R01CA159859 and R01NS106155. W.A.W. was supported by the NIH grants R01NS089868, U01CA217864, and P30CA82103; Brain Tumour Charity grant GN356; the Evelyn and Mattie Anderson Chair; the Ross K. MacNeill Foundation; the Pediatric Brain Tumor Foundation; the V Foundation; and the Samuel G. Waxman Foundation. Conceptualization, M.H. J.T. A.S. and W.A.W.; Methodology, M.H. J.T. and P.K.; Writing – Original Draft, M.H. J.T. A.S. and W.A.W.; Writing – Review & Editing, M.H. J.T. A.S. and W.A.W.; Validation: M.H. J.T. Q.Z. A.H.G. H.W. N.S. P.K. A.S.M. and N.S.; Formal Analysis: M.H. J.T. A.H.G. H.W. J.C. F.M.G.C. L.C. J.J.P. and A.S.M.; Investigation: M.H. J.T. Q.Z. M.L.M. T.Z. E.K.N. L.K.M. Z.A. F.Y. Y.T. H.A. B.L. S.I. C.Y. K.M.K. and S.M. Pollard; Resources: Y.T. B.S.M. T.M. N.S. P.K. P.D. M.P.S. D.A.L. Y.J.C. F.J.S. A.S.M. M.K. S.M. Pfister, M.D.T. A.S. and W.A.W.; Visualization: M.H. J.T. A.H.G. H.W. J.C. and J.J.P.; Supervision: F.J.S. A.S.M. M.K. S.M. Pfister, M.D.T. A.S. and W.A.W.; Project Administration: M.H. J.T. J.C. A.S. and W.A.W.; Funding Acquisition, M.H. J.T. P.D. A.S. and W.A.W. W.A.W. is a co-founder of StemSynergy Therapeutics.
Publisher Copyright:
© 2019 The Authors
Keywords
- SHH
- human pluripotent stem cells
- medulloblastoma
- neuroepithelial stem cells
PubMed: MeSH publication types
- Journal Article