Dataset Information

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

ABSTRACT: 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.

SUBMITTER: Susanto E

PROVIDER: S-EPMC7443968 | biostudies-literature | 2020 Aug

REPOSITORIES: biostudies-literature

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

Susanto Evelyn E Marin Navarro Ana A Zhou Leilei L Sundström Anders A van Bree Niek N Stantic Marina M Moslem Mohsen M Tailor Jignesh J Rietdijk Jonne J Zubillaga Veronica V Hübner Jens-Martin JM Weishaupt Holger H Wolfsberger Johanna J Alafuzoff Irina I Nordgren Ann A Magnaldo Thierry T Siesjö Peter P Johnsen John Inge JI Kool Marcel M Tammimies Kristiina K Darabi Anna A Swartling Fredrik J FJ Falk Anna A Wilhelm Margareta M

Proceedings of the National Academy of Sciences of the United States of America 20200803 33

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 <i>PTCH1.</i> We found that Gorlin NES cells formed tumors in mouse cerebellum mimicking human medulloblastoma. Retransplantation of tumor-isolated NES (tNES) cells resulted in accelerated tumo ...[more]

PMID: 32747535

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Project description:Sonic hedgehog (Shh) signaling is critical during development and its aberration is common across the spectrum of human malignancies. In the cerebellum, excessive activity of the Shh signaling pathway is associated with the devastating pediatric brain tumor medulloblastoma. We previously demonstrated that exaggerated de novo lipid synthesis is a hallmark of Shh-driven medulloblastoma and that hedgehog signaling inactivates the Rb/E2F tumor suppressor complex to promote lipogenesis. Indeed, such Shh-mediated metabolic reprogramming fuels tumor progression, in an E2F1- and FASN-dependent manner. Here, we show that the nutrient sensor PPAR? is a key component of the Shh metabolic network, particularly its regulation of glycolysis. Our data show that in primary cerebellar granule neural precursors (CGNPs), proposed medulloblastoma cells-of-origin, Shh stimulation elicits a marked induction of PPAR? alongside major glycolytic markers. This is also documented in the actively proliferating Shh-responsive CGNPs in the developing cerebellum, and PPAR? expression is strikingly elevated in Shh-driven medulloblastoma in vivo. Importantly, pharmacological blockade of PPAR? and/or Rb inactivation inhibits CGNP proliferation, drives medulloblastoma cell death and extends survival of medulloblastoma-bearing animals in vivo. This coupling of mitogenic Shh signaling to a major nutrient sensor and metabolic transcriptional regulator define a novel mechanism through which Shh signaling engages the nutrient sensing machinery in brain cancer, controls the cell cycle, and regulates the glycolytic index. This also reveals a dominant role of Shh in the etiology of glucose metabolism in medulloblastoma and underscores the function of the Shh ? E2F1 ? PPAR? axis in altering substrate utilization patterns in brain cancers in favor of tumor growth. These findings emphasize the value of PPAR? downstream of Shh as a global therapeutic target in hedgehog-dependent and/or Rb-inactivated tumors.

Dataset Information

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

Publications

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

Similar Datasets

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