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

胶质母细胞瘤（GBM）是中枢神经系统最常见、最致命的恶性肿瘤。GBM 细胞迅速增殖并弥漫性浸润大脑，这些特性使这些肿瘤大部分 无法治愈为了有效地控制GBM，肿瘤细胞侵袭和增殖的机制必须 被新疗法所理解和靶向。EGFR-Ras和PI-3激酶的组成性激活 （PI 3 K）信号通路是人类GBM中的常见特征，并且足以引起胶质母细胞瘤样细胞凋亡。 小鼠模型中的表型。这些信号通路如何特异性地控制神经胶质的发病机制， 不清楚建立了一种新的果蝇模型，以了解EGFR和PI 3 K驱动的分子基础。 GBM。当使用遗传技术靶向神经胶质和神经胶质前体时，EGFR和PI 3 K的共激活 在果蝇中，神经胶质细胞会产生肿瘤性的、侵袭性的神经胶质细胞，产生可移植的肿瘤样生长。 模仿人类的疾病这种模式！已被用于识别神经胶质瘤形成的新调节因子 通过基因筛选和表型分析。在这些中鉴定的新基因的人类直系同源物 筛选评估了它们在人类GBM中的参与，因为它们代表了优秀的候选者 直接参与发病机制的基因我的研究结果揭示了非典型激酶，它们是 GBM细胞的增殖和存活，并且这些激酶中的一种足以转化GBM细胞， 永生化星形胶质细胞。我的研究结果表明，这些激酶的过度表达产生了一个前馈回路， 促进和维持GBM细胞转化，该环的破坏触发GBM细胞凋亡 细胞对这些激酶的研究旨在阐明它们在转化中的特定作用， 果蝇和哺乳动物系统中的EGFR-PI 3 K信号传导。

Glioblastoma (GBM) is the most common and deadly malignant tumor of the centrail nervous system. GBM cells proliferate rapidly and diffusely infiltrate the brain, properties which render these tumors largely incurable. To effectively control GBM, the mechanisms underlying tumor cell invasion and proliferation must be understood and targeted with novei therapies. 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 df EGFR and PI3K driven GBM. When targeted to glia and glial precursors using genetic techniques, co-activation of EGFR and PI3K in Drosophila gives rise to neoplastic, invasive glial cells that create transplantable tumor-like growths^ mimicking the human disease. This mode! has been used to identify new regulators of glial neoplasia through genetic screens and phenotypic analyses. Human orthologs of novel genes identified in these screens were assessed for their involvement in human GBM because they represent excellent candidates for genes directly involved in the pathogenesis. My results reveal atypical kinases that are necessary forthe proliferation and survival of GBM cells, and that one of these kinases sufficient for transformation of irnmortalized astrocytes. My results suggest that overexpression of these kinases creates a feedforward loop that promotes and maintains GBM cell transformation, and disruption of this loop triggers apoptosis of GBM cells. Proposed iStudies of these kinases are aimed,at elucidating their specific roles in transformation and EGFR-PI3K signaling in both Drosophila and mammalian systems.