Modeling SHH-driven medulloblastoma with patient iPS cell-derived neural stem cells
| Autor: | Susanto, Evelyn, Navarro, Ana Marin, Zhou, Leilei, Sundström, Anders, van Bree, Niek, Stantic, Marina, Moslem, Mohsen, Tailor, Jignesh, Rietdijk, Jonne, Zubillaga, Veronica, Huebner, Jens-Martin, Weishaupt, Holger, Wolfsberger, Johanna, Alafuzoff, Irina, Nordgren, Ann, Magnaldo, Thierry, Siesjo, Peter, Johnsen, John Inge, Kool, Marcel, Tammimies, Kristiina, Darabi, Anna, Johansson, Fredrik K., Falk, Anna, Wilhelm, Margareta |
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| Jazyk: | angličtina |
| Rok vydání: | 2020 |
| Předmět: |
Medical Sciences
Neurologi Galectin 1 Pyridines Cell- och molekylärbiologi medulloblastoma Mice Neural Stem Cells Cell Line Tumor Animals Humans Anilides Hedgehog Proteins neural stem cells Cell Proliferation Cancer och onkologi disease model Basal Cell Nevus Syndrome Neoplasms Experimental Biological Sciences Gene Expression Regulation Neoplastic Patched-1 Receptor stomatognathic diseases Neurology Cancer and Oncology Cell and Molecular Biology |
| Zdroj: | Proceedings of the National Academy of Sciences of the United States of America |
| ISSN: | 1091-6490 0027-8424 |
| Popis: | Significance Here we describe and utilize a model of medulloblastoma, a malignancy accounting for 20% of all childhood brain cancers. We used iPS-derived neural stem cells with a familial mutation causing aberrant SHH signaling. We show that these cells, when transplanted into mouse cerebellum, form tumors that mimics SHH-driven medulloblastoma, demonstrating the development of cancer from healthy neural stem cells in vivo. Our results show that reprogramming of somatic cells carrying familial cancer mutations can be used to model the initiation and progression of childhood cancer. 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. |
| Databáze: | OpenAIRE |
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