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      Matrix stiffness drives Epithelial-Mesenchymal Transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway

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          Abstract

          Matrix stiffness potently regulates cellular behavior in various biological contexts. In breast tumours, the presence of dense clusters of collagen fibrils indicates increased matrix stiffness and correlates with poor survival. It is unclear how mechanical inputs are transduced into transcriptional outputs to drive tumour progression. Here we report that TWIST1 is an essential mechano-mediator that promotes epithelial-mesenchymal transition (EMT) in response to increasing matrix stiffness. High matrix stiffness promotes nuclear translocation of TWIST1 by releasing TWIST1 from its cytoplasmic binding partner G3BP2. Loss of G3BP2 leads to constitutive TWIST1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT and promote tumour invasion and metastasis. In human breast tumours, collagen fiber alignment, a marker of increasing matrix stiffness, and reduced expression of G3BP2 together predict poor survival. Our findings reveal a TWIST1-G3BP2 mechanotransduction pathway that responds to biomechanical signals from the tumour microenvironment to drive EMT, invasion, and metastasis.

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          Most cited references28

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          Epithelial-mesenchymal transitions in development and disease.

          The epithelial to mesenchymal transition (EMT) plays crucial roles in the formation of the body plan and in the differentiation of multiple tissues and organs. EMT also contributes to tissue repair, but it can adversely cause organ fibrosis and promote carcinoma progression through a variety of mechanisms. EMT endows cells with migratory and invasive properties, induces stem cell properties, prevents apoptosis and senescence, and contributes to immunosuppression. Thus, the mesenchymal state is associated with the capacity of cells to migrate to distant organs and maintain stemness, allowing their subsequent differentiation into multiple cell types during development and the initiation of metastasis.
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            Tensional homeostasis and the malignant phenotype.

            Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
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              Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures.

              The three-dimensional culture of MCF-10A mammary epithelial cells on a reconstituted basement membrane results in formation of polarized, growth-arrested acini-like spheroids that recapitulate several aspects of glandular architecture in vivo. Oncogenes introduced into MCF-10A cells disrupt this morphogenetic process, and elicit distinct morphological phenotypes. Recent studies analyzing the mechanistic basis for phenotypic heterogeneity observed among different oncogenes (e.g., ErbB2, cyclin D1) have illustrated the utility of this three-dimensional culture system in modeling the biological activities of cancer genes, particularly with regard to their ability to disrupt epithelial architecture during the early aspects of carcinoma formation. Here we provide a collection of protocols to culture MCF-10A cells, to establish stable pools expressing a gene of interest via retroviral infection, as well as to grow and analyze MCF-10A cells in three-dimensional basement membrane culture.
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                Author and article information

                Journal
                100890575
                21417
                Nat Cell Biol
                Nat. Cell Biol.
                Nature cell biology
                1465-7392
                1476-4679
                14 May 2015
                20 April 2015
                May 2015
                01 November 2015
                : 17
                : 5
                : 678-688
                Affiliations
                [1 ]Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0819
                [2 ]The Biomedical Sciences Graduate Program, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0819
                [3 ]Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0819
                [4 ]Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0819
                [5 ]Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0819
                [6 ]Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive, La Jolla, California, 92093-0819
                Author notes
                [* ]Correspondence should be addressed to J.Y. ( jingyang@ 123456ucsd.edu )
                [7]

                These authors contributed equally to this work.

                [#]

                Current address: Department of Immunology, The University of Texas MD Anderson Cancer Center, 7455 Fannin Street, Houston, Texas, 77030

                Article
                NIHMS671664
                10.1038/ncb3157
                4452027
                25893917
                b935ddb7-69d2-483e-8efb-c6cb36aa62b3
                History
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                Cell biology
                Cell biology

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