Chemotaxis in pancreatic ductal adenocarcinoma metastasis: An unexpected role of N-WASP in receptor trafficking
: Pancreatic ductal adenocarcinoma is one of the most invasive and metastatic cancers and has a dismal 5-year survival rate. We find that N-WASP is required for the metastatic process, with roles in chemotaxis, steering cells out of primary tumours, and matrix remodelling. Lysophosphatidic acid (LPA), a signalling lipid abundant in blood and ascites fluid, is both a mitogen and chemoattractant for PDAC cells. Pancreatic cancer cells efficiently break LPA down as they respond to it, setting up a self-generated gradient that directs cells out of the tumour. N-WASP depleted cells are unable to respond to LPA gradients and show altered RhoA activation, leading to a loss of cell contractility and traction forces, and reduced metastasis in vitro and in vivo. N-WASP couples LPA receptor signalling to RhoA via the endocytic adapter SNX18, and promotes sensitivity by preventing receptor degradation and promoting recycling of the LPA receptor back to the cell surface. We highlight N-WASP as a central controller of a chemotactic loop between PDAC cells and microenvironmental conditions that drives metastasis.
professor of cell biology
Professor of Cell Biology, CRUK Beatson Institute and Deputy Director Institute of Cancer Sciences, University of Glasgow, UK
Domain 4 - UMR 144 - Cell Biology and Cancer