Control of Medulloblastoma Migration & Survival by Unc5c

髓母细胞瘤是儿童最常见的恶性脑肿瘤。它的快速增长和发展趋势 通过神经系统传播使其极难治疗，超过40%的儿童 罹患这种疾病的人会死于这种疾病。髓母细胞瘤的改进治疗很可能来自更深层次的 了解控制正常小脑发育的信号，并欣赏这些信号是如何 肿瘤中的信号是不受调控的。 为了识别这些信号，我们研究了髓母细胞瘤的动物模型？？修补突变小鼠。 -并确定了与颗粒细胞前体相比，在肿瘤细胞中表达发生变化的基因 (GCPs)，被认为是肿瘤产生的细胞。在表达下降的基因中 最重要的是UncSc，它编码Netrin信号分子家族的受体。UncSc 最初被描述为细胞迁移的调节器，但最近被证明发挥着重要的作用 在细胞凋亡中的作用也是如此。此外，UncSc在多种癌症中被缺失或突变，因此 被认为是一种肿瘤抑制因子。我们假设UncSc控制着移民和 GCP在小脑正常发育过程中的存活，其丢失是导致异常的原因之一 在髓母细胞瘤中观察到迁移和存活率增加。如果这一假设是正确的，它将有 对我们理解髓母细胞瘤的重要意义，并为治疗髓母细胞瘤开辟新的途径 这种疾病。为了检验我们的假设，我们建议： 1)确定UncSc是否调节颗粒细胞前体和肿瘤细胞的向内迁移 2)检测UncSc是否调节颗粒细胞前体细胞和肿瘤细胞的存活 3)确定髓母细胞瘤的形成是否需要失去UncSc 与公共卫生的相关性： 髓母细胞瘤治疗中最大的挑战之一是肿瘤细胞迁移到 它们通常不会去的地区，并在它们到达那里后生存下来。我们观察到的改变 UncSc在髓母细胞瘤中的表达意义重大，因为它可以促进这两种行为。通过 阐明UncSc在迁移和生存中的作用，我们的研究将揭示分子 髓母细胞瘤侵袭性生长和扩散的机制。这反过来又会 为开发可用于抗击这种毁灭性疾病的新疗法铺平道路。

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.