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

描述(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，这表明可能会在启动和维持这些细胞的突变中找到有效新治疗的靶点。室管膜瘤包括一组不同的肿瘤，发生在儿童和成人的整个中枢神经系统(CNS)。这些肿瘤经常抵抗常规治疗，在高达40%的患者中是无法治愈的。因此，为了确定室管膜瘤潜在的新治疗方法，我们分类鉴定了这种疾病的起源细胞(S)以及将这些细胞转化为CSC的突变。通过比较肿瘤和发育中神经系统的基因表达谱，我们发现，来自中枢神经系统不同部位的室管膜瘤具有胚胎神经系统相应区域神经前体细胞的基因表达谱，称为放射状胶质细胞(RG)。我们还表明，室管膜瘤是由CSC传播和维持的，这与RG非常相似，而且来自CNS不同部分的室管膜瘤包含解剖部位特异的染色体变化。因此，我们假设中枢神经系统不同部分的RG是室管膜瘤起源的细胞，并且容易获得不同的基因突变，将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，这些研究将使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)使用我们已经从230例室管膜瘤样本中建立的500K单核苷酸多态图谱阵列图谱来确定该病的候选癌基因和肿瘤抑制基因(TSG)。2)从中枢神经系统的不同区域激活RG中的候选癌基因和敲除候选TSG，以确定这些细胞是否易转化为CSC。对CSC特性的评估将包括不受约束的自我更新和肿瘤启动能力。3)在遗传性小鼠模型的RG中，同时激活Notch1信号和Ink4a/Arf缺失，这是我们在人脑内室管膜瘤中观察到的。与公共卫生相关：迫切需要有效的室管膜瘤新疗法。通过定义室管膜瘤的起源细胞和转化这些细胞的突变，这项提议的目的将带来对这种疾病的深刻理解，并为新的治疗确定分子靶点。

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.