human TMA caseResearch

Primary brain tumors are caused by genetic mutations that perturb key developmental and homeostatic processes in the central nervous system. Our lab seeks to understand the cellular and genetic logic underlying these diseases in order to gain new insights into neurodevelopment and neurophysiology that can contribute to improved treatment and diagnosis. Glioblastoma (GBM), the most common and deadly primary brain tumor, displays signature genetic lesions that activate the EGFR tyrosine kinase and the PI-3 kinase (PI3K) pathways. How these pathways drive tumorigenesis is unclear, and how to effectively target these pathways therapeutically remains to be determined. Thus, new therapeutic targets and new therapeutic strategies must be uncovered that both inhibit EGFR or PI3K signaling pathways and actively stimulate the death of GBM cells.

Our research program is designed to discover new regulators of GBM using a multidisciplinary approach. To this end, we developed a novel GBM model in Drosophila melanogaster in which glial progenitor cells give rise to invasive neoplastic tumors in response to constitutive co-activation of the EGFR and PI3K pathways. Fluro BrainTo find new pathways that govern EGFR- and PI3K- dependent glial tumorigenesis, we performed genetic screens using our Drosophila model, from which we isolated several novel kinases that are required for neoplastic glial proliferation. Human orthologs of these novel kinases have been assessed for involvement in GBM using bioinformatics, neuropathology, and functional analysis in mammalian GBM model systems. Our results revealed that several novel kinases are subject to genetic mutations and/or altered expression in human GBM tumors. Ongoing studies of these kinases are aimed at elucidating their roles in tumorigenesis and EGFR-PI3K signaling in both Drosophila and mammalian systems.

Our research demonstrates that glial progenitor cells that normally create a neurogenic niche are prone to neoplastic transformation by EGFR-Ras and PI3K signaling. Transformation of these niche glia involves pathways that are normally required for the proper development of neural stem cells. Our ongoing studies of the niche glia and the signals that drive their tumorigenic transformation will bring new insights into the basic biology of neurogenesis as well as the cellular and genetic origins of human brain cancers.