Effect of Microenvironmental Mechanical Signals On Epithelial-Mesenchymal Transition

Epithelial-mesenchymal transition (EMT), a phenotypic alteration in which epithelial cells detach from their surroundings and become migratory, is important in many developmental processes and is co-opted in neoplastic progression. Matrix metalloproteinase-3 (MMP3), a stromally expressed enzyme that is upregulated in many breast tumors, induces EMT in cultured mammary cells and EMT, fibrosis, and carcinogenesis in the mammary gland in vivo. We show here that cell shape and matrix compliance are critical determinants of mammary epithelial cell fate in response to MMP3. Culturing cells on substrata with varying compliances reveals that soft substrata, with compliances comparable to that of the normal mammary gland, are protective against MMP3-mediated EMT, whereas stiffer substrata, with compliances comparable to that of the average breast tumor, promote EMT. Results provide insight into how biophysical properties of the cellular microenvironment contribute to EMT and will aid in future identification of therapeutic targets for blocking MMP-mediated fibrosis and malignancy in vivo.