Drosophila Glioblastoma Model to Study Signaling Pathways

Objective: Glioblastoma (GBM) is a highly aggressive and malignant brain tumorthat has limited treatment options and has an extremely poor prognosis(Waghmare et al. 2014). The amplification of Epidermal Growth Factor Receptor-VIII (EGFR-VIII) and activation of the Phosphatidyl Inositol 3-Kinase (PI3K)pathway are common genetic alterations observed in GBM patients (An et al.2018). Our objective is to model GBM in Drosophila melanogaster and study thesignaling pathways that promote GBM growth and inhibit cell death. Specifically,we aim to investigate the roles of MAPK, Hippo, and WNT signaling pathways inregulating GBM growth and Cactus expression, which regulates the JNK pathway.Methods: Our project involves genetic crosses that produce larvae with GBM,followed by brain dissections and immunohistochemistry to study changes insignaling pathways that promote GBM growth. Specifically, we are studying theearly time points to understand the roles of signaling pathways like MAPK, Hippo,and WNT in promoting GBM growth and/or inhibiting cell death. By comparing ourGBM models to experimental controls, we aim to generate initial data for designingfurther genetic experiments to identify specific signaling interactions that affect celldeath and proliferation. We will use two lines, (1) y w UAS PI3K92E; +; Repo-Gal4 and (2)UAS GFP/TM3B,Sb, and (2) y w; UAS EGFRλtop/TM6C, to generate glioma inDrosophila, and investigate whether the Hippo pathway regulates Cactus, whichalso regulates the JNK pathway.Significance: The proposed research has significant implications for understandingthe molecular mechanisms underlying GBM growth and identifying key molecules andpathways that drive this deadly disease. Using Drosophila as a model systemallows for efficient genetic manipulation and provides a cost-effective way to studycomplex biological processes. Additionally, the results of this study will contributeto our understanding of GBM.