Epithelial Cell Polarity & Tissue Maintenance

Most of our organs consist of epithelial cells, which are able to adhere to one another to form tissues. Because these cells are so common, it is not surprizing that most cancers come from epithelial tissues, including the intestine, kidney, breast pancreas, lung and skin to name a few. In order to form tissues and stay in place, epithelial cells need to form adhesion domains on their sides so that they can stick to their neighbours. Having formed adhesion domains, these cells can now make their top surface different from their bottom surface. Together with adhesion, the polarization of the epithelial cells is needed for them to work properly. Loss of polarity and adhesion is a hallmark of cancer and pathologists have long relied on assessing epithelial cell shape to diagnose of this disease. Work in our research group focuses on uncovering the mechanisms that regulate polarity and adhesion in epithelial cells. By understanding these mechanisms we will be able to figure out what goes wrong with these cells when cancer arises, and we will be better equipped to prevent or fix the problem.

Apical-basal polarity is essential for epithelial cell function, and in epithelial tissues its loss is a hallmark of cancer. The overall aim of our research group is to elucidate how polarity arises in epithelial cells and how it is maintained in mature tissues. To this end we combine work in Drosophila tissues and human cell lines, using optogenetic, biophysical methods and super resolution imaging approaches. With this three-year funding support, our goal is to address the following specific aims: (1) Explore the extent to which regulated nuclear export of polarity factors acts as a main mechanism of cell polarity in animal cells. We have obtained evidence that regulated RanGTP-dependent nucleocytoplasmic transport and in particular release of the polarity protein PAR4/LKB1 from the nuclear export machinery regulates epithelial polarity. We will determined how exactly this new polarity mechanism operates and how widespread it’s function is during polarized cell morphogenesis (2) Test whether the PAR complex acts as a receptor for the exocyst to translate polarity at the cell cortex into plasma membrane morphogenesis, including cell-cell contact maturation. We have recently discovered that in components of the conserved PAR complex binds to subunit of the exocyst. The exocyst is an octameric complex that is conserved across phyla and promotes membrane delivery, raising the possibility that the PAR complex regulates cargo delivery during polarized morphogenesis. Altogether, our two research aims to elucidate the mechanisms that generate epithelial polarity and maintain epithelial tissue integrity, a prerequisite for understanding epithelial cells function and how defects in polarity and tissue integrity impact on human diseases such as cancer.