From cells to cures : neural stem cells unveil the mechanisms and therapeutic vulnerabilities of SHH-medulloblastoma

Cancer initiation and progression is an intricate and multifaceted process starting from normal cells exposed to oncogenic events, progressing to neoplastic clones, and ultimately becoming tumor cells. Cancer research during past decades has relied heavily on models such as established cancer cell lines, surgically removed tumors and patient-derived xenograft models (PDXs), which represent the end stage of tumor development. Due to species differences, genetically engineered mouse models (GEMMs) cannot fully recapitulate human tumors. Therefore, tumor initiation and early progression has remained as a challenging area of study until the emergence of induced pluripotent stem cells (iPSCs) technology which has revolutionized disease modeling and therapies discovery. Here we present examples demonstrating the potential of iPSCs-derived neural stem cells in modeling SHH-driven medulloblastoma (MB), investigating molecular mechanisms underlying tumor initiation and early progression, and screening drugs to identify effective therapies and targets.iPSC-derived neuroepithelial stem (NES) cells have a hindbrain identity and mimic the neural stem cells of embryonic and fetal cerebellum. NES cells with a germline PTCH1 mutation behave like normal neural stem cells under normal culture conditions whereas exhibit growth advantages in 3D environments and under hypoxia. Serial orthotopic transplantation of mutant NES cells results in tumors mimicking human SHH-MB in histology and transcriptome. The tumor NES (tNES) cells exhibit increased cell migration and invasion and decreased dependency on growth factors (Paper I). During tumor progression, various epigenetic and genetic changes were identified which may contribute to tumorigenesis either alone or in conjunction with PTCH1 mutation (Paper II). Using NES-based high-throughput drug screening platform, we screened a library of compounds of known targets and identified that S6K1 inhibition can selectively target MB tumor cells while sparing normal neural stem cells and neurons (Paper III). Using the same screening platform for a library of 33,000 novel compounds, we identified a series of novel compounds demonstrating potential efficacy and selectivity for tumor cells over normal healthy cells (Unpublished results).In summary, our work demonstrated the potential of iPSC-derived neural stem cells in modeling SHH-MB, understanding molecular mechanisms of MB tumor initiation and early progression, and identifying effective therapies and targets.List of scientific papersI. 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. Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells. Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):20127-20138. https://www.doi.org/10.1073/pnas.1920521117II. Zhou L, Oksanen M, Mastropasqua F, Tammimies K, Wilhelm M. Revealing Sequential Epigenetic and Genetic Changes in Medulloblastoma Pathogenesis Using PTCH1-Mutant Neural Stem Cell Models. ManuscriptIII. Zhou L, van Bree N, Boutin L, Ryu J, Moussaud S, Liu M, Otrocka M, Olsson M, Falk A, Wilhelm M. High-throughput neural stem cell-based drug screening identifies S6K1 inhibition as a selective vulnerability in SHH-medulloblastoma. Neuro Oncol. 2024 Sep 5;26(9):1685-1699. https://www.doi.org/10.1093/neuonc/noae104