A Drosophila Model for EGFR-Ras and PI3K-Dependent Human Glioma

Abstract

Gliomas, the most common malignant tumors of the nervous system, frequently harbor mutations that activate the epidermal growth factor receptor (EGFR) and phosphatidylinositol-3 kinase (PI3K) signaling pathways. To investigate the genetic basis of this disease, we developed a glioma model in Drosophila. We found that constitutive coactivation of EGFR-Ras and PI3K pathways in Drosophila glia and glial precursors gives rise to neoplastic, invasive glial cells that create transplantable tumor-like growths, mimicking human glioma. Our model represents a robust organotypic and cell-type-specific Drosophila cancer model in which malignant cells are created by mutations in signature genes and pathways thought to be driving forces in a homologous human cancer. Genetic analyses demonstrated that EGFR and PI3K initiate malignant neoplastic transformation via a combinatorial genetic network composed primarily of other pathways commonly mutated or activated in human glioma, including the Tor, Myc, G1 Cyclins-Cdks, and Rb-E2F pathways. This network acts synergistically to coordinately stimulate cell cycle entry and progression, protein translation, and inappropriate cellular growth and migration. In particular, we found that the fly orthologs of CyclinE, Cdc25, and Myc are key rate-limiting genes required for glial neoplasia. Moreover, orthologs of Sin1, Rictor, and Cdk4 are genes required only for abnormal neoplastic glial proliferation but not for glial development. These and other genes within this network may represent important therapeutic targets in human glioma. Malignant gliomas, tumors composed of glial cells and their precursors, are the most common and deadly human brain tumors. These tumors infiltrate the brain and proliferate rapidly, properties that render them largely incurable even with current therapies. Mutations in genes within the EGFR-Ras and PI3K signaling pathways are common in malignant gliomas, although how these genes specifically control glial pathogenesis is unclear. To investigate the genetic basis of this disease, we developed a glioma model in the fruit fly, Drosophila melanogaster. We found that constitutive coactivation of the EGFR-Ras and PI3K pathways in Drosophila glia gives rise to highly proliferative and invasive neoplastic cells that create transplantable tumor-like growths, mimicking human glioma. This represents a robust cell-type-specific Drosophila cancer model in which malignant cells are created by mutations in genetic pathways thought to be driving forces in a homologous human cancer. Genetic analyses demonstrated that EGFR-Ras and PI3K induce fly glial neoplasia through activation of a combinatorial genetic network composed, in part, of other genetic pathways also commonly mutated in human glioma. This network acts synergistically to coordinately stimulate cellular proliferation, protein translation, and inappropriate migration. Rate-limiting genes within this network may represent important therapeutic targets in human glioma.