Control of Medulloblastoma Migration & Survival by Unc5c

点击翻译按钮获取中文摘要

Medulloblastoma is the most common malignant brain tumor in children. Its rapid growth and tendency to spread through the nervous system make it extremely difficult to treat, and more than 40% of the children who develop the disease die from it. Improved treatment of medulloblastoma is likely to come from a deeper understanding of the signals that control normal cerebellar development, and an appreciation of how these signals are dysregulated in tumors. To identify such signals, we have studied an animal model of medulloblastoma - the patched mutant mouse - and identified genes whose expression is altered in tumor cells compared to granule cell precursors (GCPs), the cells from which the tumor is believed to arise. Among the genes whose expression decreased most significantly was UncSc, which encodes a receptor for the netrin family of signaling molecules. UncSc was originally described as a regulator of cell migration, but has recently been shown to play an important role in apoptosis as well. Moreover, UncSc is deleted or mutated in a variety of cancers, and has therefore been suggested to function as a tumor suppressor. We hypothesize that UncSc controls migration and survival of GCPs during normal cerebellar development, and that its loss contributes to the abnormal migration and increased survival observed in medulloblastoma. If this hypothesis is correct, it will have important implications for our understanding of medulloblastoma, and open up new avenues for treatment of the disease. To test our hypothesis, we propose to: 1) Determine whether UncSc regulates inward migration of granule cell precursors and tumor cells 2) Test whether UncSc regulates survival of granule cell precursors and tumor cells 3) Determine whether loss of UncSc is required for medulloblastoma formation Relevance to Public Health: One of the greatest challenges in medulloblastoma treatment is the ability of tumor cells to migrate into regions where they would not normally go, and to survive once they get there. Our observation of altered UncSc expression in medulloblastoma is significant because it can contribute to both of these behaviors. By elucidating the role of UncSc in migration and survival, our studies will shed light on the molecular mechanisms that underlie the aggressive growth and dissemination of medulloblastoma. This, in turn, will pave the way for developing new treatments that can be used to fight this devastating disease.