Research Project
10353664
Project Summary/Abstract Medulloblastoma (MB) is a fast-growing and heterogeneous brain tumor arising in the cerebellum. Group 3, one of four MB subgroups (WNT, SHH, Group 3, and Group 4), is the most aggressive and malignant type in children. Group 3, accounting for 25%-30% of all MB, is characterized by frequent metastasis at diagnosis and the worst prognosis. Although surgical resection, radiotherapy, and chemotherapy are effective at eliminating some forms, patients with Group 3 cannot be cured with conventional therapies and also face a paucity of molecularly targeted therapies. The overall objective in this application is to define the molecular mechanisms that regulate tumor metastatic dissemination in Group 3. Candidate pathways are critically needed to provide rational leads for enabling new and effective therapies for children with MB. Preliminary studies reveal that SMARCD3/BAF60C (SMARCD3 hereafter), a core component of SWI/SNF chromatin-remodeling complexes, is highly expressed in Group 3 MB and Purkinje cells (PCs) of the developing cerebellum. Furthermore, elevated SMARCD3 expression is associated with patient poor outcomes, MB metastatic phenotype, and activation of the Reelin signaling pathway that is required for PC migration and positioning in cerebellar development. The central hypothesis of this application is that the SMARCD3-associated SWI/SNF chromatin-remodeling complex regulates Reelin signaling pathway in PC migration and positioning during cerebellar development; however, this neurodevelopmental program is hijacked for MB metastatic dissemination. The central hypothesis will be tested by pursuing two specific aims: 1) investigate the role of SMARCD3 in PC migration and positioning during cerebellar development; and 2) define the mechanism linking SMARCD3-Reelin signaling to metastatic phenotype in MB. Under the first aim, a new mouse model will be generated by crossing the Smarcd3 flox/flox mouse with a PC-specific gene promoter (L7/Pcp2)-driven Cre mouse. The role of SMARCD3-associated SWI/SNF chromatin-remodeling complexes in cerebellar development will be investigated using this mouse model. For the second aim, in vitro and in vivo gain/loss-of-function approaches in human MB cell lines and xenograft mouse models will be used to test SMARCD3-Reelin signaling-mediated tumor metastatic dissemination. Additionally, ATAC- and ChIP-sequencing will be performed to determine how SMARCD3- associated SWI/SNF complexes regulate the Reelin signaling pathway. The research proposed in this application is innovative because it focuses on understanding the role of SMARCD3 in both neurodevelopment and medulloblastoma, and the prospect of tumor cells hijacking neurodevelopmental signaling resulting in metastasis. The proposed research is significant because it is expected to provide compelling functional evidence of SMARCD3 and the associated SWI/SNF complexes? involvement in cerebellar development, tumor metastasis, and the molecular connections between early brain development and tumorigenesis. Ultimately, such knowledge has the potential of offering new rationales for the development of innovative therapies for patients with MB.
