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CURATOR
A pinboard by
Laurent FATTET

Postdoctoral fellow, UCSD - Moores Cancer Center

PINBOARD SUMMARY

Increased stiffness drives breast tumor invasion and metastasis via mechanoregulation of Twist1.

Mechanical forces were recently recognized as potent regulatory signals of cellular behavior in various biological contexts. Matrix stiffness is controlled by deposition and modification of the extracellular matrix. Breast tumors are often detected due to their apparent “hardness” compared to normal tissues, and we and others have previously shown that increasing matrix stiffness correlates with disease progression and poor survival. These observations raise the question of how mechanical forces generated by the microenvironment impact tumor progression and metastasis. Mammary epithelial cells form normal ductal acini with stable adherens junctions and intact basement membrane mimicking normal mammary ducts in the compliant matrix stiffness whereas they present weaker junctions and invade through basement membrane in the rigid stiffness similar to breast tumors. These cell morphological changes in response to increasing mechanical forces resemble the Epithelial-Mesenchymal Transition (EMT) program. Here we show that the transcription factor Twist1 is an essential mechano-mediator that promotes EMT in response to increasing extracellular matrix (ECM) stiffness. High ECM stiffness promotes nuclear translocation of Twist1 by releasing Twist1 from its novel cytoplasmic binding partner G3BP2. We identified the kinase responsible for phosphorylating Twist1 within the G3BP2-binding motif. Inhibition (pharmacological inhibition and shRNA-mediated downregulation) of the identified kinase blocks ECM stiffness-induced EMT and restores the interaction between Twist1 and G3BP2. Loss of G3BP2 in mammary epithelial cells leads to constitutive Twist1 nuclear localization and synergizes with increasing matrix stiffness to induce EMT, local invasion, and metastatic dissemination to the lungs in breast tumor xenografts. In human breast tumors, collagen fiber alignment, a marker of increasing matrix stiffness, and reduced expression of G3BP2 together predict poor survival. In summary, our study identifies a novel mechanotransduction pathway that regulates the subcellular localization of the EMT transcription factor Twist1 to drive EMT and invasion during breast tumor progression. Our ongoing study aims to uncover the upstream sensors and transmitters that convert mechanical signals from the microenvironment to regulate the interaction between Twist1 and G3BP2 in response to increasing ECM stiffness.