Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis

Miller Huang, Jignesh Tailor, Qiqi Zhen, Aaron H. Gillmor, Matthew L. Miller, Holger Weishaupt, Justin Chen, Tina Zheng, Emily K. Nash, Lauren K. McHenry, Zhenyi An, Fubaiyang Ye, Yasuhiro Takashima, James Clarke, Harold Ayetey, Florence M.G. Cavalli, Betty Luu, Branden S. Moriarity, Shirin Ilkhanizadeh, Lukas ChavezChunying Yu, Kathreena M. Kurian, Thierry Magnaldo, Nicolas Sevenet, Philipp Koch, Steven M. Pollard, Peter Dirks, Michael P. Snyder, David A. Largaespada, Yoon Jae Cho, Joanna J. Phillips, Fredrik J. Swartling, A. Sorana Morrissy, Marcel Kool, Stefan M. Pfister, Michael D. Taylor, Austin Smith, William A. Weiss

Research output: Contribution to journalArticlepeer-review

22 Scopus citations

Abstract

Huang, Tailor, et al. show that neuroepithelial stem (NES) cells derived from normal induced pluripotent stem cells (iPSCs) provide a renewable human cell-based resource to evaluate genetic mutations in medulloblastoma. Misexpression of MYCN in both otherwise-normal NES cells and PTCH1+/− NES cells derived from patients with Gorlin syndrome each generated medulloblastoma in mice.

Original languageEnglish (US)
Pages (from-to)433-446.e7
JournalCell Stem Cell
Volume25
Issue number3
DOIs
StatePublished - 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 (Universit? de Nice Sophia Antipolis) and Association Ren? Tourraine, Fondation ARC (SFI201212055859), the Fondation de l'Avenir, the Soci?t? Fran?aise 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

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