The Drosophila retina as a model for human cancer: Identification of genes that mediate oncogenic tyrosine kinase signaling

Tyrosine kinases play critical roles in development and disease. In mammals, the Ret receptor tyrosine kinase (RTK) primarily functions in nervous system and renal development. In humans, Ret mutations cause a wide array of diseases and developmental abnormalities. In particular, dominant mutations in the Ret RTK cause the cancer syndrome Multiple Endocrine Neoplasia type 2 (MEN2). Mammalian tissue culture studies suggest that RetMEN2 mutations significantly alter Ret signaling properties, but how this causes disease remains poorly understood. To determine the signal transduction pathways required for RetMEN2 activity, I have studied analogous mutations in the Drosophila Ret ortholog, dRet. I generated flies that overexpress dRetMEN2 isoforms in the developing retina, which causes aberrant cell proliferation, inappropriate cell fate specification, and excessive Ras pathway activation. I performed a genetic screen for suppressors and enhancers of the dRet MEN2 phenotypes and through this screen I identified numerous genes that function in dRet signal transduction. In a unique collaboration with Dr. Paul Goodfellow's lab, MEN2 associated tumors were examined for genetic alterations in the human orthologs of dRet modifiers with the goal of identifying new tumor suppressors that function in MEN2.; Through this screen, I discovered a new Drosophila tumor suppressor, the Drosophila Csk ortholog, dCsk. Csk family cytoplasmic tyrosine kinases encode critical negative regulators of Src family kinases. Src kinases regulate multiple cellular processes including differentiation, proliferation, and oncogenesis. I demonstrate that the Drosophila Csk ortholog, dCsk, functions as a crucial modulator of growth and proliferation: dCsk mutants display organ overgrowth and excess cellular proliferation. Genetic analysis indicates that the dCsk−/− overgrowth phenotype results from activation of Src, Jun kinase, and STAT signal transduction pathways. In particular, blockade of STAT function in dCsk mutants severely reduced Src-dependent overgrowth and activated apoptosis of mutant tissue. My data provide in vivo evidence that Src activity requires Jun kinase and STAT function. Furthermore, my data suggest that inhibition of STAT function may be sufficient to activate Src-dependent apoptosis of transformed tissue. The role of dCsk, Src, and STAT in dRet signaling and ‘transformation’ is now being explored.