Abstract 5760: Identifying cell of origin for Group 3 medulloblastoma

Medulloblastoma (MB) is the most common malignant pediatric brain tumor. Although surgery, radiation and high-dose chemotherapy have led to increased survival rates, many patients still die from their disease and those who survive often suffer severe long-term side effects. Group 3 MB is the most aggressive subtype of MB, which is often resistant to therapy, and patients with this tumor have an extremely poor prognosis. Thus, developing novel and more effective therapeutic approaches is desperately needed for treating this disease. Improved approaches are likely to come from a deeper understanding of the molecular and cellular basis of the disease. Group 3 MB is characterized by large cell/anaplastic histology with a high proliferative index and is associated with MYC amplification or overexpression. Our previous studies suggest that MYC-driven MB can be generated by infecting granule neuron progenitors (GNPs, Math1+) or neonatal cerebellar stem cells/progenitors (CD133+) with viruses encoding MYC and dominant negative p53 (DNp53) and transplanting these cells into the cerebella of immunocompromised mice (NSG). Although this model resembles Group 3 MB in terms of histology and gene expression, it most likely does not faithfully recapitulate human MB because mutation and deletion of p53 are rarely detected in human Group 3 MB at diagnosis. This observation prompted us to ask whether there might be a cell type in which the MYC oncogene alone is sufficient to induce MB. Sox2 expression has been found in neural stem cell/progenitor cells in cerebellum. Moreover, it has been reported that ~70% human Group 3 MB express Sox2, and that its expression is correlated with poor prognosis. Thus we hypothesize that Sox2-positive cells with MYC overexpression can develop tumors. We FACS-sorted Sox2GFP-positive or Sox2GFP-negative cells from Sox2-GFP mice at P5, infected these cells with MYC virus and transplanted them into the cerebella of NSG mice. Animals (n=10) receiving Sox2-positive cells developed highly aggressive tumors and had to be sacrificed within 3-6 weeks. In contrast, only one of the animals (n=10) that received Sox2-negative cells developed a tumor at 8 weeks. These results suggest that the MYC oncogene alone is sufficient to induce tumorigenesis in Sox2-positive cells, without requiring loss of p53. Further studies demonstrate that the tumors that were generated from Sox2-positive cells resemble Group 3 MB at a histological, immunohistochemical and molecular level, indicating that Group 3 MB may originate from Sox2-positive cells during cerebellar development. We will use this model to investigate the mechanisms that make these cells sensitive to transformation. These studies will pave the way for the development of novel approaches to treating this devastating tumor. Citation Format: Ran Tao, Najiba Murad, Zhenhua Xu, Yanxin Pei. Identifying cell of origin for Group 3 medulloblastoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 5760. doi:10.1158/1538-7445.AM2017-5760