A Model for Glioma in Drosophila

描述（由申请人提供）：神经胶质瘤是中枢神经系统最常见和最致命的恶性肿瘤。神经胶质瘤细胞弥漫性地浸润邻近的并且通常是远处的脑结构，这一特性使得它们在很大程度上无法治愈。为了有效地控制胶质瘤，必须确定肿瘤细胞侵袭和进展的潜在机制，并采用新的治疗方法进行靶向治疗。然而，控制渗透的信号在很大程度上是未知的。小鼠模型和人类组织培养模型已经为胶质瘤中已知的遗传改变的作用提供了有价值的见解，但是由于难以进行正向遗传筛选，它们尚未被广泛用于发现参与胶质瘤发病机制的新基因。本项目的目标是在果蝇中建立神经胶质瘤模型，目的是进行大规模的遗传筛选，以确定参与神经胶质瘤侵袭和进展的基因。果蝇神经胶质细胞与哺乳动物神经胶质细胞有许多共同的特性，包括在EGFR-Ras和PIS激酶信号通路共激活时显示浸润性神经胶质瘤样肿瘤表型。在这个项目中，候选基因座牵连在人类胶质细胞将被评估和新的调节EGFR-Ras/PI 3激酶诱导的侵袭性将被搜索。已知在神经胶质瘤中上调的基因的果蝇直向同源物，但其在发病机制中的作用是未知的，将在神经胶质细胞中特异性地错误表达，并测定神经胶质瘤样表型。将进行增强或抑制EGFR-Ras和PIS激酶途径激活后的神经胶质瘤样侵袭性表型的突变的筛选，并确定相应基因的身份。在这些筛选中鉴定的基因将代表直接参与发病机制的基因的优秀候选者。相关性：这些研究有望为胶质瘤发病机制提供关键见解，包括参与肿瘤细胞迁移和侵袭的基因的身份。这些基因的产物可能是治疗的极好靶点。

DESCRIPTION (provided by applicant): Gliomas are the most common and deadly malignant tumors of the central nervous system. Glioma cells diffusely infiltrate adjacent and often distant brain structures, a property which renders them largely incurable. To effectively control gliomas, the mechanisms underlying tumor cell invasion and progression must be determined and targeted with novel therapies. However, the signals that govern infiltration are largely unidentified. Mouse models and human tissue culture models have provided valuable insights into the roles of known genetic alterations in glioma, but because of the difficulty in carrying out forward genetic screens, they have not been widely used to discover new genes involved in glioma pathogenesis. The goal of this project is to create a model of glioma in the fruit fly Drosophila for the purpose of carrying out large- scale genetic screens to identify genes involved in glioma invasion and progression. Drosophila glia share many properties with mammalian glia, including the display of infiltrative, glioma-like tumor phenotypes upon co-activation of the EGFR-Ras and PIS kinase signaling pathways. In this project, candidate loci implicated in human gliogenesis will be evaluated and novel regulators of EGFR-Ras/PI3 kinase-induced invasiveness will be searched for. Drosophila orthologs of genes known to be upregulated in glioma, but whose roles in pathogenesis are unknown, will be misexpressed specifically in glial cells and assayed for glioma-like phenotypes. A screen for mutations that enhance or suppress the glioma-like invasive phenotype upon EGFR-Ras and PIS kinase pathway activation will be carried out and the identity of the corresponding genes will be established. The genes identified in these screens will represent excellent candidates for genes directly involved in pathogenesis. Relevance: These studies are expected to provide key insights into glioma pathogenesis, including the identity of genes involved in tumor cell migration and invasiveness. The products of these genes may represent excellent targets for therapeutics.