Cellular and Genetic Basis of Anaplastic Medulloblastoma

描述(申请人提供)：髓母细胞瘤(MB)是儿童最常见的恶性脑肿瘤。肿瘤表现为大细胞/间变性(LCA)组织学的患者通常治疗失败并死于他们的疾病。治疗这些患者的改进方法可能来自对LCA肿瘤的更深入了解，包括它们的侵袭性生长特性以及它们的侵袭和转移行为。遗憾的是，人LCA MB组织很难获得，现有的MB基因工程小鼠(GEM)模型很少显示间变或转移。为了解决这个问题，我们收集了100个人类LCA MB，包括成对的原发/转移肿瘤样本。此外，我们还建立了基于GEM和移植的LCA MB模型，并动员了转座因子睡美人(SB)来促进这些模型中的再生和转移。通过对人类和小鼠数据集的分析，我们建议确定驱动LCA髓母细胞瘤进展的细胞和基因。这项应用汇集了来自三个机构的研究人员，他们在神经发育、干细胞生物学和人类和小鼠MB基因组学方面都有共同的经验。我们互补的背景和专业知识使我们在研究LCA MB的细胞和分子基础方面具有独特的地位，并最终将使我们能够开发更有效的方法来针对这些侵袭性肿瘤。 公共卫生相关性：建议的研究集中在大细胞/间变性髓母细胞瘤，这是一种高度恶性的儿童脑瘤，预后极差。通过识别导致这种肿瘤侵袭行为的细胞和基因，我们希望开发出更有效的治疗方法。

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is the most common malignant brain tumor in children. Patients whose tumors exhibit large cell/anaplastic (LCA) histology usually fail therapy and die from their disease. Improved approaches to treating these patients are likely to come from a deeper understanding of LCA tumors, including their aggressive growth properties and their invasive and metastatic behavior. Unfortunately, human LCA MB tissue is difficult to obtain, and existing genetically engineered mouse (GEM) models of MB rarely display anaplasia or metastasis. To address this problem, we have collected >100 human LCA MBs, including paired samples of primary/metastatic tumors. In addition, we have generated GEM and transplant-based models of LCA MB, and mobilized the transposable element Sleeping Beauty (SB) to promote anaplasia and metastasis in these models. Through analysis of our human and murine datasets, we propose to identify the cells and genes that drive progression in LCA medulloblastoma. This application brings together investigators from three institutions, with collective experience in neural development, stem cell biology and genomics of both human and murine MB. Our complementary backgrounds and expertise uniquely position us to investigate the cellular and molecular basis of LCA MB, and will ultimately allow us to develop more effective approaches to targeting these aggressive tumors. PUBLIC HEALTH RELEVANCE: The proposed studies focus on large cell/anaplastic medulloblastoma, a highly malignant pediatric brain tumor with an extremely poor prognosis. By identifying the cells and genes responsible for the aggressive behavior of this tumor, we hope to develop more effective approaches to therapy.