Abstract
SummaryHuman 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.
Highlights
Neural stem cell culture systems could potentially advance our understanding of human brain development and disease (Gage, 2000)
MYCN Drives Transformation of Normal Human induced pluripotent stem cell (iPSC)-Derived NES Cells to Sonic Hedgehog (SHH) Medulloblastoma We first asked whether neuroepithelial stem (NES) cells can be transformed into brain-tumor-initiating cells by a known driver of medulloblastoma
Amplification of MYCN correlates with high-risk SHH medulloblastoma, and MYCN can drive medulloblastoma in germline and non-germline genetically engineered mouse models (GEMMs) (Swartling et al, 2010; 2012)
Summary
Neural stem cell culture systems could potentially advance our understanding of human brain development and disease (Gage, 2000). The capture of self-renewing neural progenitor cells in vitro provides scalable cell populations for biochemical or genetic studies. Neural stem cells can be genetically manipulated or differentiated in a controlled environment. Cell Stem Cell 25, 433–446, September 5, 2019 a 2019 The Authors.
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