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

EGFR-Ras和PI-3激酶（PI3K）信号通路的组成性激活是人类GBM的共同特征，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地控制神经胶质的发病机制尚不清楚。为了了解EGFR和PI3K驱动的GBM的分子基础，我们创建了一个新的果蝇模型。当使用遗传技术靶向胶质细胞和胶质前体时，果蝇中EGFR和RISK的共同激活会产生肿瘤，侵入性胶质细胞，产生可移植的肿瘤样生长，模拟人类疾病。遗传分析表明，EGFR和PI3K诱导果蝇神经胶质瘤的部分原因是通过一个组合遗传网络，其中包括在人类GBM中通常突变或激活的基因和途径。该模型已被用于通过遗传筛选和表型分析来确定神经胶质瘤形成的新调控因子。在这些筛选中鉴定的基因代表了直接参与人类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细胞系中研究果蝇修饰物的哺乳动物同源物的表达和功能。在指导期间，一个已经确定的果蝇修饰基因及其哺乳动物同源性将在果蝇和哺乳动物系统中进行详细分析。这些研究将在我的导师、果蝇神经生物学专家约翰·托马斯博士、我的合作者、老鼠遗传学专家和癌症生物学家因德·维尔马博士和我的共同导师约翰·托马斯博士的实验室里进行。Webster Cavenee和Frank Furnari都是GBM生物学方面的专家。这将为我提供必要的培训，以便在一所研究密集型医学院获得独立教员的职位，在那里我将扩展这些研究，包括另外2-3个基因。公共卫生相关性：这些研究有望提供胶质瘤发病机制的关键见解，包括参与肿瘤细胞迁移和侵袭性的基因的身份。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.