Growth Control and Tumor Suppression

The final size of epithelial organs is tightly regulated during the development of many animals, and in insects in particular size control seems to be intrinsic to the organ itself. How epithelial cells communicate to each other to measure the size of the organ as a whole, and to make a communal decision to cease proliferation, is an outstanding mystery. We are exploring the unknown pathways by which organ size is controlled, and in particular how the unique features of epithelial architecture promote the restraint of excess growth.

Cell polarity and proliferation appear coupled in a number of contexts, and disruption of epithelial polarity correlates with the progression of malignant tumors. The causal relationship or mechanism of such coupling has been obscure. We have advanced and framed the hypothesis that alterations of cell polarity can have a causative contribution to inappropriate cell division, and demonstrated that this is indeed true in the simple and experimentally amenable system of the Drosophila neoplastic tumor suppressor genes (TSGs). We are currently using this system to address a number of interesting questions, including: What factors lie downstream of neoplastic tumor suppressors to affect growth, and what are the mechanisms underlying their inappropriate regulation? Why does exit from cell cycle and determination of organ size require epithelial organization? Are factors other than conventional cell-cell signaling pathways involved? What are the downstream targets of these signaling pathways that control growth?

We have designed and executed an efficient forward genetic screen that isolates not only new polarity regulators but also new TSGs. Amongst the TSGs we have identified are those encoding core components of the endocytic pathway. Mutants in these genes show polarity and proliferation phenotypes nearly identical to those of the original ‘junctional scaffold’ neoplastic TSGs. The endocytic mutants also have distinct and fascinating effects on signal transduction by canonical intercellular signaling pathways. We are exploring how endocytosis regulates these canonical signaling pathways, specifically in the context of Notch receptor trafficking, which has a particular influence on growth control. We are also cloning and characterizing more novel TSGs with different mechanisms of growth control.