(49c) Melanoma-Induced Endothelial Barrier Disruption Via VE-Cadherin Disassembly and Cell Contractility

Metastasis is a complex process whereby cancer cells detach from the primary tumor and migrate to remote locations within the body through the vascular and lymphatic systems. During metastasis, breakdown of endothelial adherens junctions is critical for tumor cell extravasation through blood vessel walls and is mediated by a combination of tumor secreted soluble factors and receptor-ligand interactions. Here, we investigate the roles of key intracellular signaling molecules and cytoskeletal contractility in regulating melanoma-induced VE-cadherin disassembly. Through the use of traction force microscopy and pharmacological inhibitors of cytoskeletal contractility we find that endothelial cell contractility is responsive to interactions with metastatic cancer cells and that reducing endothelial cell contractility abrogates melanoma-mediated disassembly of endothelial cell-cell junctions. Furthermore, we find that a combination of tumor secreted soluble factors and receptor-ligand interactions mediate activation of Src within endothelial cells which is necessary for breakdown of the endothelial barrier. Together, these results provide insight into how tumor cell signals act in concert during extravasation and may aid in identification of therapeutic targets to block metastasis.