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

EGFR-RAS和PI-3激酶(PI3K)信号通路的结构性激活是人类GBM的共同特征，足以在小鼠模型中产生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。建立了一种新的果蝇模型，以了解EGFR和PI3K驱动的GBM的分子基础。当使用基因技术靶向胶质细胞和胶质前体时，EGFR和Risk在果蝇中的共同激活会产生肿瘤、侵袭性胶质细胞，从而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PI3K诱导果蝇胶质瘤的部分原因是通过组合遗传网络，其中包括在人类GBM中也常见的突变或激活的基因和途径。这个模型已经被用来通过基因筛查和表型分析来识别神经胶质瘤的新调节因子。在这些筛选中发现的基因代表了直接参与人类GBM发病机制的基因的极佳候选基因。因此，将在人类肿瘤、基因定义的小鼠GBM和GBM细胞系中检测果蝇修饰物的哺乳动物同源基因的表达和功能。在指导的几年中，一个已经确定的果蝇修饰基因及其哺乳动物同源基因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、果蝇神经生物学家约翰·托马斯博士、我的合作者、老鼠遗传学家和癌症生物学家Inder Verma博士以及我的共同导师Webster Cavenee博士和Frank Furnari博士的实验室进行，他们都是大脑皮层生物学方面的专家。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一个独立的教员职位，在那里我将扩大这些研究，纳入另外2-3个基因。公共卫生相关性：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有关的基因的识别。这些基因的产物可能是治疗的极佳靶点。

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.