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The Role of Biochemical and Mechanical Signals In Epithelial-Mesenchymal Transition

Qike Kyle Chen1, Celeste M. Nelson1, and Derek C. Radisky2. (1) Chemical Engineering, Princeton University, Princeton, NJ 08544, (2) Mayo Clinic Cancer Center, Jacksonville, FL 32224

Epithelial-mesenchymal-transition (EMT) is a characteristic phenotypic alteration in which epithelial cells detach from their neighbors and become invasive. EMT is essential for proper embryonic development, but the process is co-opted by cells during pathological conditions including fibrosis and neoplastic progression. Matrix metalloproteinase-3 (MMP3) induces EMT, fibrosis, and tumor formation in the mammary gland in vivo and in cultured mammary epithelial cells. We have used micropatterning approaches to investigate how the biochemical and mechanical properties of the microenvironment contribute to EMT. Mouse mammary epithelial cells are able to undergo EMT in response to MMP3 when cultured on fibronectin, but only if the underlying substratum permits cellular extension. Altering the identity of the extracellular matrix (collagen I, laminin-111, etc.) changes the EMT response. Understanding these microenvironmental controls will permit construction of an in vitro model of fibrosis genesis, and could reveal novel therapeutic strategies.