Engineering Genetic Predisposition in Human Neuroepithelial Stem Cells Recapitulates Medulloblastoma Tumorigenesis.

Graphical abstract from Huang, et al (2019).

Huang et al. (2019) Cell Stem Cell. CC BY 4.0

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, Weiss WA.

Cell Stem Cell

September 05, 2019

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.

Last updated: June 28, 2020