A Model for Glioma in Drosophila

描述(申请人提供)：胶质瘤是最常见和最致命的中枢神经系统恶性肿瘤。胶质瘤细胞弥漫地渗透到邻近的和通常是远处的大脑结构，这一特性使它们在很大程度上是无法治愈的。为了有效地控制胶质瘤，必须确定肿瘤细胞侵袭和进展的机制，并以新的治疗方法为靶点。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为已知的基因改变在胶质瘤中的作用提供了有价值的见解，但由于进行正向遗传筛选的难度，它们尚未被广泛应用于发现与胶质瘤发病机制有关的新基因。该项目的目标是在果蝇体内建立胶质瘤模型，以进行大规模的基因筛选，以确定参与胶质瘤侵袭和进展的基因。果蝇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信号通路的共同激活下表现出浸润性的、胶质瘤样的肿瘤表型。在这个项目中，将评估与人类胶质形成有关的候选基因，并寻找新的EGFR-RAS/PI3激酶诱导的侵袭性调节因子。已知在胶质瘤中上调的基因在果蝇中的同源基因，但其在发病机制中的作用尚不清楚，将在胶质细胞中特异地错误表达，并检测胶质瘤样表型。将对增强或抑制胶质瘤样侵袭性表型的EGFR-RAS和PIS激酶途径激活的突变进行筛选，并建立相应基因的鉴定。在这些筛选中发现的基因将代表直接参与发病机制的基因的优秀候选基因。相关性：这些研究有望为胶质瘤的发病机制提供关键的见解，包括与肿瘤细胞迁移和侵袭性相关的基因的识别。这些基因的产物可能是治疗的极佳靶点。

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.