N-WASP control of LPAR1 trafficking establishes response to self-generated LPA gradients to promote pancreatic cancer cell metastasis

Juin, A. et al. (2019) N-WASP control of LPAR1 trafficking establishes response to self-generated LPA gradients to promote pancreatic cancer cell metastasis. Developmental Cell, 51(4), 431-445.e7. (doi: 10.1016/j.devcel.2019.09.018) (PMID:31668663) (PMCID:PMC6863394)

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Pancreatic ductal adenocarcinoma is one of the most invasive and metastatic cancers and has a dismal 5-year survival rate. We show that N-WASP drives pancreatic cancer metastasis, with roles in both chemotaxis and matrix remodeling. lysophosphatidic acid, a signaling lipid abundant in blood and ascites fluid, is both a mitogen and chemoattractant for cancer cells. Pancreatic cancer cells break lysophosphatidic acid down as they respond to it, setting up a self-generated gradient driving tumor egress. N-WASP-depleted cells do not recognize lysophosphatidic acid gradients, leading to altered RhoA activation, decreased contractility and traction forces, and reduced metastasis. We describe a signaling loop whereby N-WASP and the endocytic adapter SNX18 promote lysophosphatidic acid-induced RhoA-mediated contractility and force generation by controlling lysophosphatidic acid receptor recycling and preventing degradation. This chemotactic loop drives collagen remodeling, tumor invasion, and metastasis and could be an important target against pancreatic cancer spread.

Item Type:Articles
Additional Information:L.M.M., R.H.I., and J.C.N. are funded by Cancer Research UK Core grants (A15673 to L.M.M., A19257 to R.H.I., and A18277 to J.C.N.). M.F.A.C. and N.G. acknowledge European Research Council funding through FAKIR 648892 consolidator award, and M.F.A.C. acknowledges financial support from the University of Glasgow MG Dunlop Bequest and College of Science and Engineering scholarship.
Glasgow Author(s) Enlighten ID:Koh, Wui Hui Yvette and Cutiongco, Ms Marie and Juin, Dr Amelie and Norman, Professor James and McGhee, Dr Ewan and Thomason, Dr Peter and Lilla, Dr Sergio and Spence, Dr Heather and Machesky, Professor Laura and Insall, Professor Robert and Mackay, Dr Gillian and Fort, Loic and Kalna, Dr Gabriela and Gadegaard, Professor Nikolaj and Neilson, Dr Matthew
Authors: Juin, A., Spence, H. J., Martin, K. J., McGhee, E., Neilson, M., Cutiongco, M. F.A., Gadegaard, N., Mackay, G., Fort, L., Lilla, S., Kalna, G., Thomason, P., Koh, Y. W.H., Norman, J. C., Insall, R. H., and Machesky, L. M.
College/School:College of Medical Veterinary and Life Sciences > School of Cancer Sciences
College of Science and Engineering > School of Engineering > Biomedical Engineering
Journal Name:Developmental Cell
Publisher:Elsevier (Cell Press)
ISSN (Online):1878-1551
Published Online:24 October 2019
Copyright Holders:Copyright © 2019 The Authors
First Published:First published in Developmental Cell 51(4):431-445.e7
Publisher Policy:Reproduced under a Creative Commons License

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Project CodeAward NoProject NamePrincipal InvestigatorFunder's NameFunder RefLead Dept
172025FAKIR: Focal Adhesion Kinetics In nanosurface RecognitionNikolaj GadegaardEuropean Research Council (ERC)648892ENG - Biomedical Engineering