Control of Medulloblastoma Migration & Survival by Unc5c

描述（申请人提供）：髓母细胞瘤是儿童最常见的恶性脑肿瘤。它的快速生长和通过神经系统扩散的趋势使其极难治疗，超过40%的患病儿童死于这种疾病。髓母细胞瘤的改善治疗可能来自于对控制正常小脑发育的信号的更深入的理解，以及对这些信号在肿瘤中如何失调的认识。为了识别这些信号，我们研究了成神经管细胞瘤的动物模型——补丁突变小鼠——并鉴定了与颗粒细胞前体（GCPs）相比，肿瘤细胞中表达改变的基因，后者被认为是肿瘤产生的细胞。在表达下降最显著的基因中，编码netrin信号分子家族受体的Unc5c。Unc5c最初被描述为细胞迁移的调节因子，但最近被证明在细胞凋亡中也起重要作用。此外，Unc5c在多种癌症中缺失或突变，因此被认为具有肿瘤抑制作用。我们假设在正常的小脑发育过程中，Unc5c控制着gcp的迁移和存活，而在成神经管细胞瘤中，Unc5c的缺失导致了gcp的异常迁移和存活的增加。如果这一假设是正确的，它将对我们对成神经管细胞瘤的认识产生重要的影响，并为该疾病的治疗开辟新的途径。为了验证我们的假设，我们提出：1)确定Unc5c是否调节颗粒细胞前体和肿瘤细胞的向内迁移2)测试Unc5c是否调节颗粒细胞前体和肿瘤细胞的存活3)确定成神经管细胞瘤形成是否需要Unc5c的缺失髓母细胞瘤治疗的最大挑战之一是肿瘤细胞迁移到它们通常不会去的区域的能力，以及一旦它们到达那里就能存活的能力。我们在成神经管细胞瘤中观察到的Unc5c表达改变是有意义的，因为它可以促进这两种行为。通过阐明Unc5c在迁移和存活中的作用，我们的研究将揭示成神经管细胞瘤侵袭性生长和传播的分子机制。反过来，这将为开发可用于对抗这种毁灭性疾病的新疗法铺平道路。

DESCRIPTION (provided by applicant): 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 Unc5c, which encodes a receptor for the netrin family of signaling molecules. Unc5c was originally described as a regulator of cell migration, but has recently been shown to play an important role in apoptosis as well. Moreover, Unc5c is deleted or mutated in a variety of cancers, and has therefore been suggested to function as a tumor suppressor. We hypothesize that Unc5c 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 Unc5c regulates inward migration of granule cell precursors and tumor cells 2) Test whether Unc5c regulates survival of granule cell precursors and tumor cells 3) Determine whether loss of Unc5c 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 Unc5c expression in medulloblastoma is significant because it can contribute to both of these behaviors. By elucidating the role of Unc5c 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.