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Matrix stiffness drives epithelial–mesenchymal transition and tumour metastasis through a TWIST1–G3BP2 mechanotransduction pathway

Nature Cell Biology volume 17, pages 678688 (2015) | Download Citation

Abstract

Matrix stiffness potently regulates cellular behaviour 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 mechanomediator 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 fibre 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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Acknowledgements

We thank members of the Yang laboratory, especially M. Eckert, for helpful discussions. We thank the UCSD Shared Microscope Facility (P30NS047101), the UCSD Cancer Center Support Grant P30CA23100, and the NCI Cancer Diagnosis Program (CDP) for providing breast tumour tissue microarrays. The shRFP control pLKO.1 plasmid was a kind gift from S. Stewart (Washington University in St Louis, USA). This work was supported by grants from NIH (DP2OD002420-01, 1RO1CA168689), DOD Breast Cancer Program W81XWH-13-1-0132, and ACS (RSG-09-282-01-CSM) to J.Y., from DOD W81XWH-13-1-0133 to A.J.E., from NIH (DK54441) and HHMI to S.S.T., and from NIH (P01AG007996) to R.L.S. S.C.W. was supported by a NIH Cancer Cell Biology Training grant (2T32CA067754), NIH Molecular Pathology of Cancer Training grant (5T32CA077109), and was an ARCS Foundation Scholar. L.F. was supported by a postdoctoral fellowship from Fondation pour la Recherche Médicale (SPE20130326547).

Author information

Author notes

    • Spencer C. Wei

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

    • Spencer C. Wei
    •  & Laurent Fattet

    These authors contributed equally to this work.

Affiliations

  1. Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA

    • Spencer C. Wei
    • , Laurent Fattet
    • , Jeff H. Tsai
    • , Vincent H. Pai
    • , Hannah E. Majeski
    • , Susan S. Taylor
    •  & Jing Yang
  2. The Biomedical Sciences Graduate Program, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA

    • Spencer C. Wei
    • , Vincent H. Pai
    •  & Hannah E. Majeski
  3. Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA

    • Yurong Guo
    •  & Susan S. Taylor
  4. Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA

    • Albert C. Chen
    • , Robert L. Sah
    •  & Adam J. Engler
  5. Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA

    • Susan S. Taylor
  6. Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA

    • Jing Yang

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Contributions

S.C.W. and J.Y. conceived the project and wrote the manuscript. S.C.W. and L.F. performed most of the experiments and prepared the figures. J.H.T., Y.G., V.H.P., H.E.M. and A.C.C. contributed to the experimental work. R.L.S., S.S.T. and A.J.E. advised on experimental design. L.F., J.H.T. and A.J.E. revised the manuscript.

Competing interests

The authors declare no competing financial interests.

Corresponding author

Correspondence to Jing Yang.

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DOI

https://doi.org/10.1038/ncb3157

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