Department of Microbiology, Tumor and Cell biology (MTC), Karolinska Institutet, 171 65 Stockholm, Sweden.
Department of Immunology, Genetics, and Pathology, Science For Life Laboratory, Uppsala University, 751 85 Uppsala, Sweden.
Proc Natl Acad Sci U S A. 2020 Aug 18;117(33):20127-20138. doi: 10.1073/pnas.1920521117. Epub 2020 Aug 3.
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 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 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.
成神经管细胞瘤是儿童中最常见的恶性脑肿瘤。在这里，我们描述了一种使用诱导多能干细胞（iPS）细胞衍生的源自 Gorlin 综合征患者的人神经上皮干细胞（NES）的成神经管细胞瘤模型，该患者携带 sonic hedgehog（SHH）受体的种系突变。我们发现 Gorlin NES 细胞在小鼠小脑形成肿瘤，模拟人类成神经管细胞瘤。肿瘤分离的 NES（tNES）细胞的再移植导致肿瘤形成加速，细胞对生长因子的依赖性降低，体外神经球形成增强，并增加对 Vismodegib 的敏感性。使用我们的模型，我们确定了是 GLI 靶基因，该基因在 Gorlin tNES 细胞和 SHH 亚组成神经管细胞瘤患者中均上调。总之，我们证明了源自 Gorlin 患者的 NES 细胞可用于模拟成神经管细胞瘤的起始和进展，并鉴定潜在的靶标。
