Engineering genetic predisposition in human neuroepithelial stem cells recapitulates medulloblastoma tumorigenesis
Summary - 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) ce...
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| Main Authors: | , , , , |
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| Format: | Article (Journal) |
| Language: | English |
| Published: |
13 June 2019
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| In: |
Cell stem cell
Year: 2019, Volume: 25, Issue: 3, Pages: 433-446.e7 |
| ISSN: | 1875-9777 |
| DOI: | 10.1016/j.stem.2019.05.013 |
| Online Access: | Verlag, Volltext: https://doi.org/10.1016/j.stem.2019.05.013 Verlag: http://www.sciencedirect.com/science/article/pii/S1934590919302176 
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| Author Notes: | 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 Chavez, Chunying 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 |
| Summary: | Summary - 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. |
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| Item Description: | Gesehen am 08.10.2019 |
| Physical Description: | Online Resource |
| ISSN: | 1875-9777 |
| DOI: | 10.1016/j.stem.2019.05.013 |