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      Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin

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          Abstract

          Cancer-associated fibroblasts (CAFs) in the tumor stroma play a key role in tumor progression. Erdogan et al. show that CAF-mediated alignment of the fibronectin matrix is a key factor promoting directional cancer cell migration.

          Abstract

          Cancer-associated fibroblasts (CAFs) are major components of the carcinoma microenvironment that promote tumor progression. However, the mechanisms by which CAFs regulate cancer cell migration are poorly understood. In this study, we show that fibronectin (Fn) assembled by CAFs mediates CAF–cancer cell association and directional migration. Compared with normal fibroblasts, CAFs produce an Fn-rich extracellular matrix with anisotropic fiber orientation, which guides the cancer cells to migrate directionally. CAFs align the Fn matrix by increasing nonmuscle myosin II- and platelet-derived growth factor receptor α–mediated contractility and traction forces, which are transduced to Fn through α5β1 integrin. We further show that prostate cancer cells use αv integrin to migrate efficiently and directionally on CAF-derived matrices. We demonstrate that aligned Fn is a prominent feature of invasion sites in human prostatic and pancreatic carcinoma samples. Collectively, we present a new mechanism by which CAFs organize the Fn matrix and promote directional cancer cell migration.

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          Most cited references54

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          Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion.

          The morphology and cytoskeletal structure of fibroblasts, endothelial cells, and neutrophils are documented for cells cultured on surfaces with stiffness ranging from 2 to 55,000 Pa that have been laminated with fibronectin or collagen as adhesive ligand. When grown in sparse culture with no cell-cell contacts, fibroblasts and endothelial cells show an abrupt change in spread area that occurs at a stiffness range around 3,000 Pa. No actin stress fibers are seen in fibroblasts on soft surfaces, and the appearance of stress fibers is abrupt and complete at a stiffness range coincident with that at which they spread. Upregulation of alpha5 integrin also occurs in the same stiffness range, but exogenous expression of alpha5 integrin is not sufficient to cause cell spreading on soft surfaces. Neutrophils, in contrast, show no dependence of either resting shape or ability to spread after activation when cultured on surfaces as soft as 2 Pa compared to glass. The shape and cytoskeletal differences evident in single cells on soft compared to hard substrates are eliminated when fibroblasts or endothelial cells make cell-cell contact. These results support the hypothesis that mechanical factors impact different cell types in fundamentally different ways, and can trigger specific changes similar to those stimulated by soluble ligands. Copyright 2004 Wiley-Liss, Inc.
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            FAK-Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly.

            Cell migration is a complex, highly regulated process that involves the continuous formation and disassembly of adhesions (adhesion turnover). Adhesion formation takes place at the leading edge of protrusions, whereas disassembly occurs both at the cell rear and at the base of protrusions. Despite the importance of these processes in migration, the mechanisms that regulate adhesion formation and disassembly remain largely unknown. Here we develop quantitative assays to measure the rate of incorporation of molecules into adhesions and the departure of these proteins from adhesions. Using these assays, we show that kinases and adaptor molecules, including focal adhesion kinase (FAK), Src, p130CAS, paxillin, extracellular signal-regulated kinase (ERK) and myosin light-chain kinase (MLCK) are critical for adhesion turnover at the cell front, a process central to migration.
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              Integrin structure, activation, and interactions.

              Integrins are large, membrane-spanning, heterodimeric proteins that are essential for a metazoan existence. All members of the integrin family adopt a shape that resembles a large "head" on two "legs," with the head containing the sites for ligand binding and subunit association. Most of the receptor dimer is extracellular, but both subunits traverse the plasma membrane and terminate in short cytoplasmic domains. These domains initiate the assembly of large signaling complexes and thereby bridge the extracellular matrix to the intracellular cytoskeleton. To allow cells to sample and respond to a dynamic pericellular environment, integrins have evolved a highly responsive receptor activation mechanism that is regulated primarily by changes in tertiary and quaternary structure. This review summarizes recent progress in the structural and molecular functional studies of this important class of adhesion receptor.
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                Author and article information

                Journal
                J Cell Biol
                J. Cell Biol
                jcb
                jcb
                The Journal of Cell Biology
                The Rockefeller University Press
                0021-9525
                1540-8140
                06 November 2017
                : 216
                : 11
                : 3799-3816
                Affiliations
                [1 ]Department of Biological Sciences, Vanderbilt University, Nashville, TN
                [2 ]Department of Surgery, Vanderbilt University, Nashville, TN
                [3 ]Department of Cell and Developmental Biology, Vanderbilt University, Nashville, TN
                [4 ]Department of Mechanical Engineering, Vanderbilt University, Nashville, TN
                [5 ]Department of Pathology, Microbiology and Immunology, Vanderbilt University, Nashville, TN
                [6 ]Department of Urologic Surgery, Vanderbilt University, Nashville, TN
                [7 ]Department of Cancer Biology, Vanderbilt University, Nashville, TN
                [8 ]Department of Surgery, NorthShore University HealthSystem, Evanston, IL
                Author notes
                Correspondence to Begum Erdogan: erdoganbeg@ 123456gmail.com
                [*]

                B. Erdogan and M. Ao contributed equally to this paper.

                Dr. Webb died on May 15, 2017.

                Author information
                http://orcid.org/0000-0001-7012-906X
                http://orcid.org/0000-0002-1546-2473
                http://orcid.org/0000-0001-5962-6479
                http://orcid.org/0000-0002-4096-8636
                http://orcid.org/0000-0002-6059-6550
                Article
                201704053
                10.1083/jcb.201704053
                5674895
                29021221
                993b2158-5de0-4ae3-966a-9681231419fd
                © 2017 Erdogan et al.

                This article is distributed under the terms of an Attribution–Noncommercial–Share Alike–No Mirror Sites license for the first six months after the publication date (see http://www.rupress.org/terms/). After six months it is available under a Creative Commons License (Attribution–Noncommercial–Share Alike 4.0 International license, as described at https://creativecommons.org/licenses/by-nc-sa/4.0/).

                History
                : 07 April 2017
                : 31 August 2017
                : 25 September 2017
                Funding
                Funded by: National Institutes of Health, DOI https://doi.org/10.13039/100000002;
                Award ID: GM117916
                Award ID: CA155572
                Award ID: R01CA206458
                Award ID: R01CA163592
                Award ID: 5P30 DK058404-13
                Award ID: GISPORE 5P50 CA095103-13
                Award ID: 5U01 CA151924
                Funded by: National Center for Research Resources, DOI https://doi.org/10.0.50.239/100000097;
                Award ID: S10RR025524
                Funded by: Vanderbilt University, DOI https://doi.org/10.13039/100006537;
                Funded by: National Science Foundation, DOI https://doi.org/10.0.50.239/100000001;
                Award ID: DGE-0909667
                Categories
                Research Articles
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                Cell biology
                Cell biology

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