How do cells determine the direction of their organization, and what signals do they use to communicate this information? Epithelial cells are organized in two directions: the apical-basal axis and the plane perpendicular to this axis, which is referred to as planar cell polarity (PCP). Despite the direct role that breakdown of cell polarity plays in metastatic cancer, the mechanisms that initiate PCP signaling are not well understood and the role that regulation of cellular adhesion plays in establishing cell polarity has not been investigated in vivo. The long-term goals of this project are to understand how cellular adhesion is regulated in complex epithelial tissues, to determine whether extracellular signals play a part in this regulation, and whether regulation of cell adhesion is required for proper PCP. We plan to test the hypothesis that the pathways that control apical-basal cell polarity and PCP work together to affect cell-cell contact and more specifically, by affecting the spatial and temporal distribution of adherens junctions. The signaling pathways that control apical-basal and planar cell polarity are both highly conserved among species, but the downstream cellular functions that are affected by these pathways vary greatly among different cell types. I hope to uncover novel mechanisms of establishing cell polarity by studying a tissue in which these processes are not well-characterized. Therefore, we have recently begun using the ventral epidermis of the Drosophila embryo to study the molecular mechanisms that control PCP. Using the embryo has allowed us to specifically test the roles of adherens junctions and polarity proteins that cause cell lethality in the systems previously used to study PCP. Altogether, our preliminary data suggest that the pathways that control both axes of cell polarity work together to stabilize and dissociate cellular adhesion junctions, and that this dynamic regulation of cell adhesion is required for the proper polarity in developing epithelial tissues. Relevance: The mechanisms that control epithelial stability are not well understood, even though the dissociation of cell-cell contacts is directly involved in the metastatic transformation of epithelial cells and 90% of all cancer deaths are caused by metastasis of primary tumors. In addition, there is no current medical treatment that can usefully prevent metastasis. This project will contribute important insights into the molecular mechanisms that go awry in metastatic cancers, since the most apparent morphological change of metastatic tumors directly involves the downregulation of epithelial-specific cellular junction proteins that we will be investigating. ? ? ?
