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Susanto E, Marin Navarro A, Zhou L, Sundström A, van Bree N, Stantic M, Moslem M, Tailor J, Rietdijk J, Zubillaga V, Hübner JM, Weishaupt H, Wolfsberger J, Alafuzoff I, Nordgren A, Magnaldo T, Siesjö P, Johnsen JI, Kool M, Tammimies K, Darabi A, Swartling FJ, Falk A, Wilhelm M
Proc. Natl. Acad. Sci. U.S.A. 117 (33) 20127-20138 [2020-08-18; online 2020-08-03]
Medulloblastoma is the most common malignant brain tumor in children. Here we describe a medulloblastoma model using Induced pluripotent stem (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. Retransplantation 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 up-regulated 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 putative targets.
PubMed 32747535
DOI 10.1073/pnas.1920521117
Crossref 10.1073/pnas.1920521117
pmc: PMC7443968
pii: 1920521117