Revealing new regulators of EGFR-P13K driven glioma proliferation and migration

EGFR-Ras和PI-3激酶（PI 3 K）信号通路的组成性激活是人GBM的常见特征，足以在小鼠模型中引起胶质母细胞瘤样表型。这些信号通路如何特异性控制神经胶质的发病机制尚不清楚。建立了一种新的果蝇模型，以了解EGFR和PI 3 K驱动的GBM的分子基础。当使用遗传技术靶向神经胶质和神经胶质前体时，果蝇中EGFR和RISK的共激活引起肿瘤性、侵袭性神经胶质细胞，其产生可移植的肿瘤样生长，模仿人类疾病。遗传分析表明，EGFR和PI 3 K诱导果蝇神经胶质瘤形成，部分是通过一个组合遗传网络，包括基因和途径也通常突变或激活人类GBM。该模型已被用于通过遗传筛选和表型分析来识别神经胶质瘤形成的新调节因子。在这些筛选中鉴定的基因代表了直接参与人GBM发病机制的基因的优秀候选者。因此，将在人类肿瘤、遗传定义的小鼠GBM和GBM细胞系中检查果蝇修饰剂的哺乳动物直系同源物的表达和功能。在指导的几年里，一个已经确定的果蝇修饰基因及其哺乳动物直系同源物将在果蝇和哺乳动物系统中进行详细的分析。这些研究将在我的导师、果蝇神经生物学家约翰·托马斯博士、我的合作者、小鼠遗传学家和癌症生物学家英德·维尔马博士以及我的共同导师韦伯斯特·卡维尼博士和弗兰克·弗纳里博士的实验室中进行，他们都是GBM生物学方面的专家。这将为我提供必要的培训，以获得在研究密集型医学院的独立教师职位，在那里我将扩大这些研究，包括另外2-3个基因。公共卫生相关性：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。

Constitutive activation of the EGFR-Ras and PI-3 kinase (PI3K) signaling pathways is a common feature in human GBM and is sufficient to cause glioblastoma-like phenotypes in mouse models. How these signaling pathways specifically control glial pathogenesis is unclear. A novel Drosophila model was created to understand the molecular basis of EGFR and PI3K driven GBM. When targeted to glia and glial precursors using genetic techniques, co-activation of EGFR and RISK in Drosophila gives rise to neoplastic, invasive glial cells that create transplantable tumor-like growths, mimicking the human disease. Genetic analyses demonstrate that EGFR and PI3K induce Drosophila glial neoplasia, in part, via a combinatorial genetic network that includes genes and pathways also commonly mutated or activated in human GBM. This model has been used to identify new regulators of glial neoplasia through genetic screens and phenotypic analyses. The genes identified in these screens represent excellent candidates for genes directly involved in the pathogenesis of human GBM. Therefore, expression and function of mammalian orthologs of Drosophila modifiers will be examined in human tumors, genetically defined mouse GBMs, and GBM cell lines. During the mentored years, one already identified Drosophila modifier gene and its mammalian ortholog will be subject to detailed analysis in both Drosophila and mammalian systems. These studies will be performed in the laboratories of my mentor, Dr. John Thomas, an expert Drosophila neurobiologist, my collaborator Dr. Inder Verma, an expert mouse geneticist and cancer biologist, and my co-mentors Drs. Webster Cavenee and Frank Furnari, both experts in GBM biology. This will provide me with the training necessary to obtain an independent faculty position at a research intensive medical school, where I will expand these studies to include another 2-3 genes. PUBLIC HEALTH 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.