Dynamic Regulation of Plasma Membrane During Cell Invasion

Abstract

Cell invasion is a complicated process vital to tissue development, immune surveillance, and disease states such as metastatic cancer. While in vitro work has presented molecular mechanisms regulating cell invasion, visualization of the process in in vivo settings provides a deeper understanding of the cell biological events of invasion. To invade, a cell must cross dense barriers of extracellular matrix and basement membrane (BM); how an invasive cell regulates its plasma membrane to facilitate breach and removal of these barriers is a poorly-understood and underconsidered question. The developmental event of C. elegans anchor cell (AC) invasion provides an in vivo model for the visualization of cell invasion. The AC, a specialized uterine cell, creates a gap in the BM separating the uterine and vulval tissues and then expands that gap through the formation of an invasive protrusion. Using live-cell imaging, RNAi screening, genome editing, and photobleaching techniques I examined the mechanisms governing plasma membrane regulation during AC invasion. In Chapter 2, I discover that the AC rapidly expands an invasive protrusion to clear underlying BM through exocytosis of lysosomes in a netrin-dependent manner. In Chapter 3, I identify a barrier to membrane diffusion formed by the BM receptor dystroglycan as being necessary for expansion of the invasive protrusion and maintenance of polarity. Chapter 4 discusses the implications of these findings and future directions.