Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells

Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using iPS cell-derived human neuroepithelial stem (NES) cells generated from a Gorlin syndrome patient carrying a germline mutation in the Sonic hedgehog (SHH) receptor PTCH1. We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Re-transplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumor formation, cells with reduced growth factor dependency, enhanced neurosphere formation in vitro, and increased sensitivity to Vismodegib. Using our model we identified LGALS1 to be a GLI target gene that is upregulated in both Gorlin tNES cells and SHH-subgroup of medulloblastoma patients. Taken together, we demonstrate that NES cells derived from Gorlin patients can be used as a resource to model medulloblastoma initiation and progression, and to identify novel putative targets. Examination of RNA expression in parental cells and cells derived from 3 primary tumors and 3 secondary tumors.