An investigation of radial glia as the source of ependymoma stem cells

描述（由申请人提供）：最近发现许多癌症是由小部分癌症干细胞（CSC）产生的，这表明有效的新治疗靶点可能在启动和维持这些细胞的突变中找到。室管膜瘤包括一组不同的肿瘤，出现在整个中枢神经系统（CNS）的儿童和成人。这些肿瘤通常抵抗常规治疗，高达40%的患者无法治愈。因此，为了确定室管膜瘤的潜在新治疗方法，我们分类以确定这种疾病的起源细胞以及将这些细胞转化为CSC的突变。通过比较肿瘤的基因表达谱与发育中的神经系统的基因表达谱，我们发现，室管膜瘤从不同部位的中枢神经系统共享的基因表达谱的神经前体细胞，称为放射状胶质细胞（RG），在相应的区域的胚胎神经系统。我们还表明，室管膜瘤的繁殖和维持CSC是非常相似的RG和室管膜瘤从不同部位的中枢神经系统包含解剖部位特异性染色体改变。因此，我们假设RG在中枢神经系统的不同部分是室管膜瘤的起源细胞，并倾向于获得不同的基因突变，这些细胞转化为室管膜瘤CSC。为了验证我们的假设，我们提出了一系列高度整合的基因组和CSC研究，这些研究将采用小鼠模型和迄今为止整理的最大的人类室管膜瘤队列。我们建议：1）利用我们已经从230例室管膜瘤标本中获得的500 K单核苷酸多态性图谱，筛选出与室管膜瘤相关的候选癌基因和肿瘤抑制基因（TSG）。2)激活候选癌基因并敲低CNS不同区域RG中的候选TSG，以确定这些细胞是否易于转化为CSC。CSC属性的评估将包括无约束的自我更新和肿瘤启动能力。3)在遗传小鼠模型的RG中进行工程化，同时激活Notchl信号传导和我们在人颅内室管膜瘤中观察到的Ink 4a/Arf缺失。与公共卫生的相关性：迫切需要室管膜瘤的有效新治疗方法。通过定义室管膜瘤的起源细胞和转化这些细胞的突变，该提案的目的将大大增加对这种疾病的理解，并确定新治疗的分子靶点。

DESCRIPTION (provided by applicant): The recent discovery that many cancers are generated by small fractions cancer stem cells (CSC) suggests that targets of effective new treatments might be found among the mutations that initiate and maintain these cells. Ependymomas include a diverse group of tumors that arise throughout the central nervous system (CNS) of children and adults. These tumors often resist conventional treatments and are incurable in up to 40% of patients. Therefore, to identify potential new therapeutic approaches for ependymoma, we sort to identify the cell(s) of origin of this disease and the mutations that transform these into CSC. By comparing the gene expression profiles of tumors with those of the developing nervous system, we found that ependymomas from the different parts of the CNS share the gene expression profiles of neural precursor cells, termed radial glia (RG), in the corresponding region of the embryonic nervous system. We showed also that ependymomas are propagated and maintained by CSC that are remarkably similar to RG and that ependymomas from the different parts of the CNS contain anatomic site-specific chromosomal alterations. Thus, we hypothesize that RG in the different parts of the CNS are cells of origin of ependymoma and are predisposed to acquire distinct gene mutations that transform these cells into ependymoma CSC. To test our hypothesis we propose a series of highly-integrated genomic and CSC studies that will employ mouse models and the largest cohort of human ependymoma tumors collated to date. We propose to: 1) Use the 500K single nucleotide polymorphism mapping array profiles that we have generated already from 230 samples of ependymoma to identify candidate oncogenes and tumor suppressor genes (TSG) of this disease. 2) Activate candidate oncogenes and knock-down candidate TSG in RG from the different regions of the CNS to determine if these cells are susceptible to be transformed into CSC. Assessment of CSC properties will include unbridled self-renewal and tumor initiating capacity. 3) Engineer in RG of a genetic mouse model, concurrent activation of Notchl signaling and Ink4a/Arf deletion that we have observed in human intracranial ependymoma. Relevance to Public Health: There is a desperate need for effective new treatments of ependymoma. By defining the cell of origin of ependymoma and the mutations that transform these cells, the Aims of this proposal will bring about a profound increase in understanding of this disease and identify molecular targets for new treatments.