title: Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway.
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.
authors.affiliation: 1] Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA [2] The Biomedical Sciences Graduate Program, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Spencer C
authors.initials: SC
authors.lastname: Wei
authors.affiliation: Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Laurent
authors.initials: L
authors.lastname: Fattet
authors.affiliation: Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Jeff H
authors.initials: JH
authors.lastname: Tsai
authors.affiliation: Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Yurong
authors.initials: Y
authors.lastname: Guo
authors.affiliation: 1] Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA [2] The Biomedical Sciences Graduate Program, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Vincent H
authors.initials: VH
authors.lastname: Pai
authors.affiliation: 1] Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA [2] The Biomedical Sciences Graduate Program, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Hannah E
authors.initials: HE
authors.lastname: Majeski
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Albert C
authors.initials: AC
authors.lastname: Chen
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Robert L
authors.initials: RL
authors.lastname: Sah
authors.affiliation: 1] Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA [2] Howard Hughes Medical Institute, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA [3] Department of Chemistry and Biochemistry, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Susan S
authors.initials: SS
authors.lastname: Taylor
authors.affiliation: Department of Bioengineering, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Adam J
authors.initials: AJ
authors.lastname: Engler
authors.affiliation: 1] Department of Pharmacology, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA [2] Department of Pediatrics, University of California, San Diego, 9500 Gilman Drive La Jolla, California 92093-0819, USA.
authors.forename: Jing
authors.initials: J
authors.lastname: Yang
mesh_terms: D021581:Active Transport, Cell Nucleus; D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000473:pathology*; D002285:Carcinoma, Intraductal, Noninfiltrating / Q000235:genetics / Q000378:metabolism* / Q000401:mortality / Q000556:secondary*; D002352:Carrier Proteins / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D021982:Cell-Matrix Junctions / Q000378:metabolism*; D003094:Collagen / Q000378:metabolism; D030541:Databases, Genetic; D018572:Disease-Free Survival; D004548:Elasticity; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D006801:Humans; D053208:Kaplan-Meier Estimate; D040542:Mechanotransduction, Cellular; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism*; D034622:RNA Interference; D016601:RNA-Binding Proteins; D012189:Retrospective Studies; D013997:Time Factors; D014162:Transfection; D059016:Tumor Microenvironment; D051879:Twist-Related Protein 1 / Q000235:genetics / Q000378:metabolism*
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D002352:Carrier Proteins; C574606:G3BP2 protein, human; D009687:Nuclear Proteins; D016601:RNA-Binding Proteins; C103173:TWIST1 protein, human; D051879:Twist-Related Protein 1; D003094:Collagen