1. Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis.
- Author
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Huang M, Tailor J, Zhen Q, Gillmor AH, Miller ML, Weishaupt H, Chen J, Zheng T, Nash EK, McHenry LK, An Z, Ye F, Takashima Y, Clarke J, Ayetey H, Cavalli FMG, Luu B, Moriarity BS, Ilkhanizadeh S, Chavez L, Yu C, Kurian KM, Magnaldo T, Sevenet N, Koch P, Pollard SM, Dirks P, Snyder MP, Largaespada DA, Cho YJ, Phillips JJ, Swartling FJ, Morrissy AS, Kool M, Pfister SM, Taylor MD, Smith A, and Weiss WA
- Subjects
- Animals, Basal Cell Nevus Syndrome metabolism, Basal Cell Nevus Syndrome pathology, Brain Neoplasms metabolism, Brain Neoplasms pathology, Carcinogenesis genetics, DEAD-box RNA Helicases genetics, Disease Models, Animal, Genetic Engineering, Genetic Predisposition to Disease, Humans, Medulloblastoma metabolism, Medulloblastoma pathology, Mice, Mice, SCID, N-Myc Proto-Oncogene Protein genetics, Neoplasm Proteins genetics, Patched-1 Receptor genetics, Stem Cell Transplantation, Transplantation, Heterologous, Basal Cell Nevus Syndrome genetics, Brain Neoplasms genetics, Medulloblastoma genetics, N-Myc Proto-Oncogene Protein metabolism, Neural Stem Cells physiology, Neuroepithelial Cells physiology, Pluripotent Stem Cells physiology
- 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., (Copyright © 2019 The Authors. Published by Elsevier Inc. All rights reserved.)
- Published
- 2019
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