Project 453357

Medulloblastoma is the most common malignant brain tumor in children. Current treatment is nonspecific and causes several side effects, leaving patients with severe and permanent neurological deficits. In this context, there is an urgent need to find therapies with fewer side effects. In 30% of cases of medulloblastoma, there is overactivation of a signaling pathway named the Hedgehog signaling pathway. This signaling pathway is necessary for the development and proliferation of certain cells in the cerebellum, the portion of the brain where medulloblastoma develops. Mutations in the Hedgehog pathway can cause the formation of medulloblastoma. One of the most common mutation is found in a gene named Patched1 (Ptch1). Our lab has shown that additional mutations in other genes can work together with Ptch1 to lead to more aggressive medulloblastoma. We have identified mutations in a gene controlling messenger RNA quality control (a phenomenon called NMD) that normally serves to minimize errors in gene expression by removing aberrant messenger RNAs. Our hypothesis is that downregulation of NMD gives an advantage to tumors by leading to an increase in the production of proteins that contribute to tumor growth. Our goal is therefore to understand how inactivation of NMD cooperates with the Hedgehog signaling pathway. Such a mechanistic understanding will help us characterize a novel tumor suppressor mechanism in medulloblastoma and potentially enable the development of new therapeutic approaches for medulloblastoma.