Cellular and Molecular Requirements for Medulloblastoma Tumorigenesis

描述（由申请人提供）：髓母细胞瘤（MB）是一种小脑神经上皮肿瘤，是儿童最常见的中枢神经系统（CNS）恶性肿瘤。虽然在过去二十年中生存率显著提高，但大约三分之一的患者仍然难以治疗，目前的治疗方案导致长期的破坏性后遗症。像其他几种肿瘤一样，MBs被认为源自一种具有干细胞样特征的细胞，即所谓的癌症干细胞（CSCs）。干细胞样癌细胞已在几种中枢神经系统肿瘤中得到证实。然而，尚不清楚肿瘤是否来源于这些细胞，仅仅是通过肿瘤基质释放的趋化因子募集到该部位，还是肿瘤团块内的细胞去分化为这些干细胞样细胞。肿瘤来源于干细胞样群体的可能性对治疗具有重要意义，因为大多数抗肿瘤方案都是针对消除具有高增殖指数的细胞，这不是某些特定类型的前体细胞（如B型巢蛋白+前体细胞）的特征。在这项研究中，将通过有条件地消融该疾病小鼠模型中的巢蛋白+前体细胞来评估MB的细胞起源。我们还将评估Ccrk在小鼠神经发育中的作用，以及BROMI和Ccrk在人促结性MB细胞增殖和致瘤潜能中的作用。我们的研究小组最近表明，Bromi影响纤毛形态和Shh信号，并与crk相关并使其稳定。这项工作将促进我们对一种重要中枢神经系统肿瘤的致病机制的理解，并可能最终促进新的诊断、预后和治疗工具的发展，以及对无处不在的Shh信号通路的机制细节有更深入的了解。此外，由于Shh错误调控发生在四分之一的人类肿瘤中，并且MB发病机制的某些方面可能可推广到其他中枢神经系统肿瘤，因此本研究的结果可能具有深远的意义。

DESCRIPTION (provided by applicant): Medulloblastoma (MB) is a neuroepithelial tumor of the cerebellum and is the most common central nervous system (CNS) malignancy in children. While survival improved dramatically over the past two decades, approximately one-third remain refractory to treatment and current regimens result in long-term devastating sequelae. MBs, like several other tumors, are thought to be derived from a cell with stem-like features, so-called cancer stem cells (CSCs). Stem-like cancer cells have been demonstrated within several tumors of the CNS. However, it is unclear whether the tumors are derived from these cells, are simply recruited to the site by chemotactic factors released by the tumor stroma or whether cells within the tumor mass de-differentiate into these stem-like cells. The possibility that tumors are derived from stem-like populations has major implications for therapy since most anti- tumor regimens are geared towards elimination of cells with high proliferative index, which is not a feature of some particular classes of precursor cells such as the type B nestin+ precursor cells. In this study the cellular origins of MB will be evaluated through conditional ablation of nestin+ precursor cells in a mouse model of the disease. We will also evaluate the role of Ccrk in mouse neural development and the roles of BROMI and CCRK in the proliferation and tumorigenic potential of human desmoplastic MB cells. Our group recently showed that Bromi affects cilia morphology and Shh signaling and that it associates with and stabilizes Ccrk. This work will advance our understanding of the pathogenic mechanism of an important CNS tumor and may ultimately facilitate development of novel diagnostic, prognostic and therapeutic tools as well as enable deeper insight into the mechanistic details of the ubiquitous Shh signaling pathway. Moreover, since Shh misregulation occurs in a quarter of all human tumors and some aspects of MB pathogenesis may be generalizable to other CNS neoplasms, the results from this study may have far-reaching implications. PUBLIC HEALTH RELEVANCE: Medulloblastoma is the most common pediatric brain malignancy with dismal long-term survival and devastating sequelae in survivors. This project will address both cellular origins and molecular requirements for the development and maintenance of the disease. Results garnered from this work will deepen our understanding of medulloblastoma, potentially other CNS tumors and may reveal novel diagnostic, prognostic and therapeutic tools.