N-WASP Control of LPAR1 Trafficking Establishes Response to Self-Generated LPA Gradients to Promote Pancreatic Cancer Cell Metastasis.

Amelie Juin,Gillian Mackay,Sergio Lilla,Yvette W.H Koh,Laura M Machesky,Loic Fort,Ewan Mcghee,Jim C Norman,Peter Thomason,Gabriela Kalna,Matthew Neilson,Nikolaj Gadegaard,Kirsty J Martin,Robert H Insall,Heather J Spence,Marie F.A Cutiongco

doi:10.1016/j.devcel.2019.09.018

Amelie Juin, Gillian Mackay + Show 14 more

Open Access

https://doi.org/10.1016/j.devcel.2019.09.018

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Abstract

SummaryPancreatic 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.

Highlights

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy, which shows poor response to existing chemotherapies and high incidence of recurrence and metastasis
N-WASP Deletion Enhances Mouse Survival of PDAC and Reduces Metastasis In human pancreatic cancer, high levels of N-WASP correlate with poor overall survival (Guo et al, 2014 and Figure S1A)
N-WASP is expressed in normal pancreas, mosaic deletion of N-WASP using Pdx1::Cre had no effect on tissue structure, nor pancreatic functions (Figure 1A; Table 1)

Summary

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is the most common pancreatic malignancy, which shows poor response to existing chemotherapies and high incidence of recurrence and metastasis. PDAC tumors show extensive fibrotic stroma containing immune cells, fibroblasts, cancer cells, and matrix (Suklabaidya et al, 2018; Vennin et al, 2018). Stiffening ECM occurs due to remodeling and activates a cascade of signaling pathways, including focal adhesion kinase (FAK) and JAK-STAT3-Rho kinase, promoting tumor progression and invasion (Rath et al, 2017; Jiang et al, 2016; Laklai et al, 2016). Inhibition of cell contractility using inhibitors of JAK or FAK, ruxolitinib, and VS-4718, respectively, or Rho-kinase (with AT13148) significantly reduces ECM deposition and tumor invasion in PDAC mouse models (Jiang et al, 2016; Laklai et al, 2016). Understanding how cell migration pathways drive tumor cell invasion and metastasis is of major clinical relevance

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