(772d) Regulation of Melanoma Induced Endothelial Gap Formation By Contractile Forces

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.  Extravasation is mediated by a combination of tumor secreted soluble factors and receptor-ligand interactions which induce VE-cadherin disassembly and actin-myosin-mediated endothelial cell contraction.  Here, we investigate the roles of key intracellular signaling molecules and cytoskeletal contractility in regulating melanoma-induced VE-cadherin disassembly.  We find that pharmacological inhibition of cytoskeletal contractility reduces melanoma-mediated gap formation in endothelial monolayers.  Likewise, through the use of traction force microscopy we find that endothelial cell contractility increases when cells are exposed to soluble factors secreted by melanoma cells.  These results provide insight into how biochemical and biophysical signals act in concert during extravasation and may aid in future identification of therapeutic targets to block metastasis.