Glioblastomas (GBMs) are highly proliferative, invasive primary brain tumors derived from glia and glial progenitor cells, and are incurable with current treatments. GBMs often possess mutations that activate epidermal growth factor receptor tyrosine kinase (EGFR) and Pi-3 kinase (PI3K) signaling pathways. Studies show that additional factors and mechanisms in the tumor and the tumor microenvironment cooperate with EFGR and PI3K mutations to drive tumorigenesis, although the identity of these factors remains unclear. To address this problem, we sought to identify proteins that, when overexpressed and secreted into the tumor microenvironment, contribute to tumor initiation and progression in glial cells transformed by constitutive co-activation of EGFR and PI3K signaling. To test the activity of secreted factors on GBM initiation and progression, we used a GBM model in the fruit fly Drosophila melanogaster in which co-activation of EGFR and PI3K drives neoplastic transformation of glial progenitor cells. In the Drosophila GBM model, tumorous glia arise in vivo in the central nervous system in live Drosophila larvae, and create large easily visualized tumors that kill their hosts in 5-6 days. Thus, this GBM model system allows us to view the effects of overexpressed secreted factors on tumorigenesis in an intact brain microenvironment. Using this Drosophila GBM model, we performed an enhancer/suppressor screen wherein individual overexpression constructs for nearly every secreted and transmembrane gene in the Drosophila genome were tested using the Gal4-UAS system for their phenotypic effects on tumor growth, tumor progression, over-all brain size, and host survival. Thus, both the cell-autonomous and cell-nonautonomous effects of the tested secreted factors were phenotypically assessed in our screen. From this screen, we identified several genes as candidate enhancers. Using immunohistochemistry and fluorescent microscopy to stain and image whole dissected brains from Drosophila larvae, we analyzed the phenotypes caused by overexpression of the candidate enhancer genes on neoplastic glia transformed by co-activation of EGFR and PI3K. The results of our screen and the phenotypes of candidate enhancers will be presented. Our findings could reveal novel genes that, if evolutionarily conserved in humans, may drive GBM initiation and progression in the brain.