Partnership for the Advancement of Cancer Research Project
Whether or not metastasis occurs can make the difference between life and death for a cancer patient and whether or not a cancer cell metastasizes lies in its ability and propensity to adhere to other cells. The presence and activity of the cell adhesion molecule E-cadherin in adherens junctions is required for integrity of epithelia and its regulation is critical for morphogenesis of epithelial-derived structures. Little wonder that unregulated E-cadherin activity has been implicated in development and progression of highly malignant invasive carcinomas. But what regulates E-cadherin expression and activity? We have discovered that the Epidermal Growth Factor Receptor (Egfr) signaling pathway, which is also associated with cancer cell invasion, regulates expression of E-cadherin and differential cell affinity in two Drosophila epithelia, the wing and eye-antennal imaginal discs. Furthermore, Egfr signaling and E-cadherin function have interrelated functions in the morphogenesis of structures such as the wing veins and ommatidia, which are derived from the wing and eye discs, respectively. The small molecule GTPase Rap1 also affects E-cadherin localization and the differentiation of Egfr-dependent cell types during both wing and eye development. In an effort to elucidate the relationships between Egfr, Rap1 and E-cadherin, we will use loss- and gain-of-function approaches to determine what role Rap1 plays in the developing wing and eye imaginal discs. We will also use a mutation-based approach to explore the effect of E-cadherin-mediated adhesion on Egfr signaling. We will use Rap1 gain-of-function phenotypes to screen for genes involved in controlling E-cadherin. Finally, we will use a microarray-based strategy to identify transcriptional targets of the Egfr signaling pathway and Rap1. The remarkable similarities between Drosophila and vertebrates in these developmental processes suggest that our discoveries will lead to new tactics in the fight against cancer.
The following questions will be addressed:
The results of these experiments will elaborate a pathway of control from Egfr signaling to cell adhesion and as such, should illuminate parallel studies in vertebrates related to the role of Egfr signaling in cell transformation and metastasis.