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

By S. Wei, Laurent Fattet, J. Tsai, Yurong Guo, Vincent H. Pai, Hannah E. Majeski, Albert C. Chen, R. Sah, Susan S. Taylor, A. Engler and 1 more. Nature Cell Biology, 2015

856 citations recorded by the source corpus.

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.

Subfields: Cell Biology, Molecular Biology, Oncology

View Paper: https://www.semanticscholar.org/paper/13574b5f9654c3a5020aec9b316d64518e7081f3

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In Cell Biology

1. E. Mojares
2. Cameron G Walker
3. K. Yeung
4. Jing Yang
5. Armando E. del Río Hernández

In Molecular Biology

1. K. Yeung
2. S. Ergün
3. Jing Yang
4. E. Henke
5. R. Nandigama
6. R. Weinberg

In Oncology

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2. S. Ergün
3. Jing Yang
4. E. Henke
5. R. Nandigama
6. R. Weinberg

Citations in the corpus

• Extracellular Matrix in the Tumor Microenvironment and Its Impact on Cancer Therapy (2020, background): “Increasing stiffness of the surrounding ECM drives EMT in breast cancer cells by promoting TWIST1 translocalization into the nucleus (Wei et al., 2015).”
• Extracellular matrix remodeling in tumor progression and immune escape: from mechanisms to treatments (2023, background): “By the way, ECM stiffness transduces mechanical signal to TWIST1, then destroys the interaction between TWIST1 and Ras-GTPase activating protein SH3 domain-binding protein 2 (G3BP2), which induces nuclear import of TWIST1 and EMT in tumor [271].”
• Role of Extracellular Matrix in Development and Cancer Progression (2018, background): “Meanwhile, when in the nucleus, they readily interact with DNA-binding transcription factors, particularly TEA domain family members (TEAD), to regulate genetic expression associated with proliferation, a key hallmark of cancer [154,155].”
• Epithelial–mesenchymal transition in tumor metastasis (2016, background): “, 2008); and extracellular matrix (ECM) stiffness (Wei et al., 2015).”