Matrix stiffness drives epithelial–mesenchymal transition and tumour metastasis through a TWIST1–G3BP2 mechanotransduction pathway
Copyright policy )Matrix stiffness drives epithelial–mesenchymal transition and tumour metastasis through a TWIST1–G3BP2 mechanotransduction pathway
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.
- University of California System United States
- Department of Bioengineering University of California San Diego United States
- University of California, San Diego United States
- Department of Pediatrics University of California San Diego United States
- University of California, San Diego United States
Mechanotransduction, 11 Medical and Health Sciences (for), Mechanotransduction, Cellular, Noninfiltrating, Elasticity (mesh), Mice, Databases, Genetic, Animals (mesh), Aetiology, Cell Nucleus (mesh), Cancer, Time Factors (mesh), Tumor, Breast Cancer (rcdc), Neoplasm Invasiveness (mesh), RNA Interference, Collagen, Epithelial-Mesenchymal Transition (mesh), SCID (mesh), Retrospective Studies (mesh), Active Transport, Cell Nucleus, SCID, Transfection, Article, Disease-Free Survival, Cell-Matrix Junctions, Signal Transducing (mesh), Genetic, Nuclear Proteins (mesh), Noninfiltrating (mesh), Humans, Retrospective Studies, 31 Biological Sciences (for-2020), Carrier Proteins (mesh), Twist-Related Protein 1, Signal Transducing, Cancer (hrcs-hc), Tumor Microenvironment (mesh), Elasticity, RNA-Binding Proteins (mesh), Neoplasm Staging (mesh), Genetic (mesh), Biochemistry and Cell Biology, Carrier Proteins, Developmental Biology, Time Factors, Women's Health (rcdc), Kaplan-Meier Estimate, Mice, SCID, Medical and Health Sciences, Cell-Matrix Junctions (mesh), Kaplan-Meier Estimate (mesh), Tumor Microenvironment, 2.1 Biological and endogenous factors, Transfection (mesh), 3101 Biochemistry and cell biology (for-2020), Developmental Biology (science-metrix), Cancer (rcdc), Humans (mesh), Disease-Free Survival (mesh), Nuclear Proteins, RNA-Binding Proteins, Adaptor Proteins, Biological Sciences, Active Transport, 06 Biological Sciences (for), Extracellular Matrix, Female, Extracellular Matrix (mesh), Tumor (mesh), Epithelial-Mesenchymal Transition, Intraductal, Breast Neoplasms, Twist-Related Protein 1 (mesh), Cell Line, Databases, Breast Neoplasms (mesh), Cell Line, Tumor, Breast Cancer, Animals, Neoplasm Invasiveness, Collagen (mesh), Neoplasm Staging, Adaptor Proteins, Signal Transducing, Cell Nucleus, Cellular (mesh), 4.1 Discovery and preclinical testing of markers and technologies (hrcs-rac), Carcinoma, 2.1 Biological and endogenous factors (hrcs-rac), 3101 Biochemistry and Cell Biology (for-2020), Carcinoma, Intraductal, Noninfiltrating, Female (mesh), Cellular, RNA Interference (mesh)
Mechanotransduction, 11 Medical and Health Sciences (for), Mechanotransduction, Cellular, Noninfiltrating, Elasticity (mesh), Mice, Databases, Genetic, Animals (mesh), Aetiology, Cell Nucleus (mesh), Cancer, Time Factors (mesh), Tumor, Breast Cancer (rcdc), Neoplasm Invasiveness (mesh), RNA Interference, Collagen, Epithelial-Mesenchymal Transition (mesh), SCID (mesh), Retrospective Studies (mesh), Active Transport, Cell Nucleus, SCID, Transfection, Article, Disease-Free Survival, Cell-Matrix Junctions, Signal Transducing (mesh), Genetic, Nuclear Proteins (mesh), Noninfiltrating (mesh), Humans, Retrospective Studies, 31 Biological Sciences (for-2020), Carrier Proteins (mesh), Twist-Related Protein 1, Signal Transducing, Cancer (hrcs-hc), Tumor Microenvironment (mesh), Elasticity, RNA-Binding Proteins (mesh), Neoplasm Staging (mesh), Genetic (mesh), Biochemistry and Cell Biology, Carrier Proteins, Developmental Biology, Time Factors, Women's Health (rcdc), Kaplan-Meier Estimate, Mice, SCID, Medical and Health Sciences, Cell-Matrix Junctions (mesh), Kaplan-Meier Estimate (mesh), Tumor Microenvironment, 2.1 Biological and endogenous factors, Transfection (mesh), 3101 Biochemistry and cell biology (for-2020), Developmental Biology (science-metrix), Cancer (rcdc), Humans (mesh), Disease-Free Survival (mesh), Nuclear Proteins, RNA-Binding Proteins, Adaptor Proteins, Biological Sciences, Active Transport, 06 Biological Sciences (for), Extracellular Matrix, Female, Extracellular Matrix (mesh), Tumor (mesh), Epithelial-Mesenchymal Transition, Intraductal, Breast Neoplasms, Twist-Related Protein 1 (mesh), Cell Line, Databases, Breast Neoplasms (mesh), Cell Line, Tumor, Breast Cancer, Animals, Neoplasm Invasiveness, Collagen (mesh), Neoplasm Staging, Adaptor Proteins, Signal Transducing, Cell Nucleus, Cellular (mesh), 4.1 Discovery and preclinical testing of markers and technologies (hrcs-rac), Carcinoma, 2.1 Biological and endogenous factors (hrcs-rac), 3101 Biochemistry and Cell Biology (for-2020), Carcinoma, Intraductal, Noninfiltrating, Female (mesh), Cellular, RNA Interference (mesh)
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