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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 678–688 (2015)Cite this article

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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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Figure 1: TWIST1 is essential for matrix-stiffness-induced EMT and invasion.
Figure 2: Matrix stiffness regulates TWIST1 nuclear localization.
Figure 3: TWIST1 and YAP nuclear localization are regulated by distinct mechanotransduction pathways.
Figure 4: Matrix stiffness regulates the interaction between TWIST1 and G3BP2 to control TWIST1 subcellular localization.
Figure 5: Loss of G3BP2 cooperates with increasing matrix stiffness to promote TWIST1 nuclear localization and EMT.
Figure 6: Loss of G3BP2 induces tumour invasion in vivo.
Figure 7: Downregulation of G3BP2 and increasing collagen organization synergistically predict poor outcome in breast cancer patients.

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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

  1. Spencer C. Wei

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

  2. Spencer C. Wei and Laurent Fattet: These authors contributed equally to this work.

Authors and 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.

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Correspondence to Jing Yang.

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Supplementary Figure 2 TWIST1 is required for matrix stiffness-induced EMT.

(A) Confocal microscopy of MCF10A cells grown in 3D culture for 5 days on varying matrix rigidities stained for Laminin V (green) and DAPI (blue) (scale bar, 50 μm). (B–C) Brightfield images of MCF10A (B) and Eph4Ras (C) cells expressing control and shTwist1 shRNAs (scale bar, 75 μm). (D) Lysates of control and shTwist expressing MCF10A cells analyzed by SDS-PAGE and probed for TWIST1 and β-Actin. (E) Quantification of invasive acini of MCF10A shTwist1 cells in 3D culture (∗∗∗, P < 0.001, unpaired two-tailed T-test with Welch’s correction, n = 50 acini/experiment, 3 independent experiments, error bars represent s.d.). (F) qPCR analysis of E-cadherin (CDH1) mRNA expression in MCF10A cells in 3D culture on PA hydrogels treated or not with 5 ng/ml TGF-β for 5 days (P < 0.05, unpaired two-tailed T-test with Welch’s correction, n = 4 independent experiments, statistics source data can be found in Supplementary Table 1, error bars represent s.d.). (G) qPCR analysis of the mRNA expression of mesenchymal markers, Fibronectin (FN1) and Vimentin (VIM), in MCF10A cells in 3D culture on PA hydrogels treated or not with 5 ng/ml TGF-β for 5 days (P < 0.05, unpaired two-tailed T-test with Welch’s correction, n = 4 independent experiments, statistics source data can be found in Supplementary Table 1, error bars represent s.d.).

Supplementary Figure 3 Mechanoregulation of Twist1 nuclear localization in Eph4Ras cells.

Brightfield images (A) and confocal images (scale bar, 50 μm) (B) of Eph4Ras cells cultured on micropatterned glass coverslips for 6 h stained for Twist1 (green) and DAPI (blue) (scale bar, 20 μm). (C) Quantification of nuclear localized Twist1 in percentage of the total cell number (#, not significant, unpaired two-tailed T-test with Welch’s correction, n = 25 cells/experiment, 3 independent experiments, error bars represent s.d.).

Supplementary Figure 4 G3BP2 is a TWIST1 binding protein that localizes in the cytoplasm.

(A) Immunoprecipitation of endogenous TWIST1 from MCF10A cell lysates resolved by SDS-PAGE and silver stained. Unique bands were identified, excised, and analyzed by mass spectrometry. (B) Confocal images of MCF10A and Bt-549 cells grown in 3D culture stained for endogenously expressed G3BP2 (red) and DAPI (blue) (scale bar, 50 μm). (C) Exogenously expressed Twist1 from 293T cell lysates was immunoprecipitated and analyzed by SDS-PAGE, and probed for G3BP2 and Twist1.

Supplementary Figure 5 G3BP2 mediates mechanoregulation of TWIST1 and EMT.

(A) Brightfield images of Eph4Ras (left panel) and MCF10A (right panel) cells expressing control and G3BP2 shRNAs (scale bar, 75 μm). (B) Confocal images of MCF10A cells expressing shRNAs against G3BP2 grown in 3D culture for 5 days on varying matrix rigidities and stained for endogenously expressed TWIST1 (green) and DAPI (blue) (scale bar, 25 μm). (C) qPCR analysis of G3bp2, Twist1 and Snai2 in Eph4Ras cells expressing control (shCtrl#1) or G3bp2 shRNAs, together with control (shCtrl#2) or Twist1 shRNA (shTwist1#5), 3D cultured under indicated matrix rigidities for 5 days (∗, P < 0.05;∗∗, P < 0.01;∗∗∗, P < 0.001, unpaired two-tailed T-test with Welch’s correction, n = 3 independent experiments, statistics source data can be found in Supplementary Table 1; double knockdown compared to the respective single knockdown, error bars represent s.d.). (D) Confocal images of MCF10A cells expressing shRNAs against G3BP2 grown in 3D culture for 5 days on varying matrix rigidities and stained for YAP1 (red) and DAPI (blue) (scale bar, 50 μm).

Supplementary Figure 6 G3BP2 is required for mechanosensing in MCF10DCIS cells.

(A) Brightfield images of MCF10DCIS cells expressing control and G3BP2 shRNAs (scale bar, 25 μm). (B) Brightfield images of MCF10DCIS cells expressing control and G3BP2 shRNAs cultured in 3D at indicated matrix rigidities for 5 days (scale bar, 150 μm). (C) Confocal images of MCF10DCIS cells expressing shRNAs against G3BP2 grown in 3D culture for 5 days on varying matrix rigidities and stained for endogenously expressed TWIST1 (green) and DAPI (blue) (scale bar, 25 μm).

Supplementary Figure 7 G3BP2 expression profile in normal and cancer human tissues.

(A) Kaplan–Meier survival curve of patients stratified by G3BP2 expression in the TCGA breast cancer dataset (TCGA_BRCA_G4502A_07_3) (P = 0.2435, Log-Rank). (B) Statistics of overall survival of patients stratified by G3BP2 expression in the TCGA breast cancer dataset (TCGA_BRCA_G4502A_07_3). (C) Kaplan–Meier curve of recurrence free survival in stage 3 breast cancer patients based on SHG imaging (∗∗, P = 0.0047, Log-Rank, n = 197 breast tumours). (D) Confocal microscopy of normal human colon luminal epithelial cells stained for G3BP2 (red) and nuclei (blue) (scale bar, 50 μm). (E,F) Correlation between G3BP2 expression and ER positivity (E) or tumour grade (F) in stage 3 breast cancer patient samples analyzed in (C) (#, not significant, Fisher’s Exact, n = 197 breast tumours, error bars represent s.d.).

Supplementary Figure 8 Uncropped Western blots images.

Supplementary Table 1 Statistical source data.
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Wei, S., Fattet, L., Tsai, J. et al. Matrix stiffness drives epithelial–mesenchymal transition and tumour metastasis through a TWIST1–G3BP2 mechanotransduction pathway. Nat Cell Biol 17, 678–688 (2015). https://doi.org/10.1038/ncb3157

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