1. Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis
- Author
-
Huang, Miller, Tailor, Jignesh, Zhen, Qiqi, Gillmor, Aaron H, Miller, Matthew L, Weishaupt, Holger, Chen, Justin, Zheng, Tina, Nash, Emily K, McHenry, Lauren K, An, Zhenyi, Ye, Fubaiyang, Takashima, Yasuhiro, Clarke, James, Ayetey, Harold, Cavalli, Florence MG, Luu, Betty, Moriarity, Branden S, Ilkhanizadeh, Shirin, Chavez, Lukas, Yu, Chunying, Kurian, Kathreena M, Magnaldo, Thierry, Sevenet, Nicolas, Koch, Philipp, Pollard, Steven M, Dirks, Peter, Snyder, Michael P, Largaespada, David A, Cho, Yoon Jae, Phillips, Joanna J, Swartling, Fredrik J, Morrissy, A Sorana, Kool, Marcel, Pfister, Stefan M, Taylor, Michael D, Smith, Austin, and Weiss, William A
- Subjects
Medical Biotechnology ,Biomedical and Clinical Sciences ,Oncology and Carcinogenesis ,Pediatric Cancer ,Genetics ,Transplantation ,Brain Disorders ,Pediatric ,Regenerative Medicine ,Brain Cancer ,Stem Cell Research - Nonembryonic - Human ,Cancer ,Neurosciences ,Human Genome ,Stem Cell Research ,Stem Cell Research - Nonembryonic - Non-Human ,Rare Diseases ,Biotechnology ,2.1 Biological and endogenous factors ,Animals ,Basal Cell Nevus Syndrome ,Brain Neoplasms ,Carcinogenesis ,DEAD-box RNA Helicases ,Disease Models ,Animal ,Genetic Engineering ,Genetic Predisposition to Disease ,Humans ,Medulloblastoma ,Mice ,Mice ,SCID ,N-Myc Proto-Oncogene Protein ,Neoplasm Proteins ,Neural Stem Cells ,Neuroepithelial Cells ,Patched-1 Receptor ,Pluripotent Stem Cells ,Stem Cell Transplantation ,Transplantation ,Heterologous ,SHH ,human pluripotent stem cells ,medulloblastoma ,neuroepithelial stem cells ,Biological Sciences ,Medical and Health Sciences ,Developmental Biology ,Biological sciences ,Biomedical and clinical sciences - 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.
- Published
- 2019