Exploring the functions of SMARCD3-Reeling signaling in the metastasis phenotype and in the subgroups transition of medulloblastoma
Medulloblastoma (MB) arises 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 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. Preliminary studies reveal that SMARCD3/BAF60C (SMARCD3 hereafter) is associated with patient poor outcomes, MB metastatic phenotype, and is required for cell migration and positioning in cerebellar development.
Project Goal:
The central hypothesis of this application is that the SMARCD3 regulates pathway in cell 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 cell migration and positioning during cerebellar development; and 2) define the mechanism linking SMARCD3-pathway to metastatic phenotype in MB. Under the first aim, a new mouse model will be generated to knock out Smarcd3 in specific cerebellar cells. The role of SMARCD3-pathway in cerebellar development will be investigated using this mouse model. For the second aim, spontaneous mouse MB models will be used to test SMARCD3-pathway-mediated tumor metastatic dissemination. Advanced techniques will be performed to determine how SMARCD3 pathway regulates the Reelin signaling pathway in development and tumor formation. 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. Ultimately, such knowledge has the potential of offering new rationales for the development of innovative therapies for patients with MB.
