(722b) Mechanical Properties of the Microenvironment Regulate Epithelial-Mesenchymal Transition

Epithelial-mesenchymal transition (EMT) is a phenotypic alteration in which epithelial cells acquire mesenchymal traits. It is increasingly appreciated that EMT, a critical event in embryonic development, contributes to pathological conditions including fibrosis and cancer metastasis. Matrix metalloproteinase-3 (MMP3), a matrix-degrading enzyme, induces EMT in culture and fibroris and tumorigenesis in vivo. The cellular microenvironment plays a critical role in tumor progression. Tissue stiffening is a known risk factor for developing breast cancer. Here we investigated the role of tissue stiffness in MMP3-induced EMT and showed that matrix compliance is a critical determinant of mammary epithelial cell fate in response to MMP3. Soft substrata with compliances comparable to that of a normal mammary gland protect cells from MMP3-induced EMT, whereas stiffer substrata with compliances comparable to that of a breast tumor promote EMT. Matrix stiffness governs EMT response by controlling the subcellular localization of key signaling intermediates. Our results demonstrate how biomechanical properties of the cellular microenvironment regulate EMT and will help identify potential therapeutic targets for MMP-mediated fibrosis and malignancy in vivo.