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Chemotaxis in Pacreatic Ductal Adenocarcinoma Metastasis: An Unexpected Role of NWASP in Maintaining Self-Generated Gradients and LPA Receptor Recycling

51 Pages Posted: 18 Jan 2019 Sneak Peek Status: Published

See all articles by Amelie Juin

Amelie Juin

Beatson Institute for Cancer Research

Heather J. Spence

Beatson Institute for Cancer Research

Kirsty J. Martin

Beatson Institute for Cancer Research

Ewan McGhee

Beatson Institute for Cancer Research

Matthew Neilson

Beatson Institute for Cancer Research

Marie F. A. Cutiongco

Beatson Institute for Cancer Research

Nikolaj Gadegaard

Beatson Institute for Cancer Research

Gillian Mackay

Beatson Institute for Cancer Research

Loic Fort

Beatson Institute for Cancer Research

Sergio Lilla

Beatson Institute for Cancer Research

Gabriela Kalna

Beatson Institute for Cancer Research

Peter Thomason

Beatson Institute for Cancer Research

Yvette W. H. Koh

Beatson Institute for Cancer Research

Jim C. Norman

Beatson Institute for Cancer Research

Robert H. Insall

Beatson Institute for Cancer Research

Laura Machesky

Beatson Institute for Cancer Research

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Abstract

Pancreatic ductal adenocarcinoma is one of the most invasive and metastatic cancers and has a dismal 5-year survival rate. Here we show that N-WASP is required for the metastatic process, with roles in both chemotaxis, steering cells out of the tumour, and matrix remodelling, allowing them to escape. Lysophosphatidic acid, a signalling lipid abundant in blood and ascites fluid, is both a mitogen and chemoattractant for PDAC cells. We find they 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 recycling the receptor back to the surface. Coordinated by N-WASP, the LPA-LPAR signalling loop promotes RhoA-mediated contractility and force generation. Perturbing this pathway chemically or by CRISPR deletion causes PDAC cells to lose their ability to invade through complex 3D environments or peritoneal explants, and remodel fibrillar collagen. We thus reveal N-WASP as a central controller of a chemotactic loop between PDAC cells and microenvironmental conditions that drives metastasis.

Keywords: Pancreatic cancer metastasis, cancer invasion, chemotaxis, cancer cell signalling, cell migration, receptor trafficking

Suggested Citation

Juin, Amelie and Spence, Heather J. and Martin, Kirsty J. and McGhee, Ewan and Neilson, Matthew and Cutiongco, Marie F. A. and Gadegaard, Nikolaj and Mackay, Gillian and Fort, Loic and Lilla, Sergio and Kalna, Gabriela and Thomason, Peter and Koh, Yvette W. H. and Norman, Jim C. and Insall, Robert H. and Machesky, Laura, Chemotaxis in Pacreatic Ductal Adenocarcinoma Metastasis: An Unexpected Role of NWASP in Maintaining Self-Generated Gradients and LPA Receptor Recycling (October 30, 2018). Available at SSRN: https://ssrn.com/abstract=3275292 or http://dx.doi.org/10.2139/ssrn.3275292
This is a paper under consideration at Cell Press and has not been peer-reviewed.

Amelie Juin

Beatson Institute for Cancer Research

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Bearsden, Glasgow G61 1BD
United Kingdom

Heather J. Spence

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Kirsty J. Martin

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Ewan McGhee

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Matthew Neilson

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Marie F. A. Cutiongco

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Nikolaj Gadegaard

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Gillian Mackay

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Loic Fort

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Sergio Lilla

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Gabriela Kalna

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Peter Thomason

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Yvette W. H. Koh

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Jim C. Norman

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Robert H. Insall

Beatson Institute for Cancer Research

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

Laura Machesky (Contact Author)

Beatson Institute for Cancer Research ( email )

Switchback Rd
Bearsden, Glasgow G61 1BD
United Kingdom

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