Matrix compliance regulates Rac1b localization, NADPH oxidase assembly, and epithelial-mesenchymal transition.
Epithelial-mesenchymal transition (EMT) is a form of epithelial plasticity implicated in fibrosis and tumor metastasis. Here we show that the mechanical rigidity of the microenvironment plays a pivotal role in the promotion of EMT by controlling the subcellular localization and downstream signaling of Rac GTPases. Soft substrata, with compliances comparable to that of normal mammary tissue, are protective against EMT, whereas stiffer substrata, with compliances characteristic of breast tumors, promote EMT. Rac1b, a highly activated splice variant of Rac1 found in tumors, localizes to the plasma membrane in cells cultured on stiff substrata or in collagen-rich regions of human breast tumors. At the membrane, Rac1b forms a complex with NADPH oxidase and promotes the production of reactive oxygen species, expression of Snail, and activation of the EMT program. In contrast, soft microenvironments inhibit the membrane localization of Rac1b and subsequent redox changes. These results reveal a novel mechanotransduction pathway in the regulation of epithelial plasticity via EMT.
Department of Chemical and Biological Engineering, Princeton University, Princeton, NJ 08544, USA.
KangAe
K
Lee
Qike K
QK
Chen
Cecillia
C
Lui
Magdalena A
MA
Cichon
Derek C
DC
Radisky
Celeste M
CM
Nelson
D000818:Animals; D001696:Biomechanical Phenomena; D001940:Breast / Q000378:metabolism / Q000473:pathology; D001943:Breast Neoplasms / Q000378:metabolism / Q000473:pathology; D002462:Cell Membrane / Q000378:metabolism; D002465:Cell Movement; D060833:Cellular Microenvironment; D058750:Epithelial-Mesenchymal Transition; D005109:Extracellular Matrix / Q000378:metabolism*; D005260:Female; D022001:Focal Adhesions / Q000378:metabolism; D006801:Humans; D019012:Integrin beta1 / Q000378:metabolism; D019278:Matrix Metalloproteinase 3 / Q000378:metabolism; D051379:Mice; D008954:Models, Biological; D019255:NADPH Oxidases / Q000378:metabolism*; D009479:Neuropeptides / Q000378:metabolism*; D011485:Protein Binding; D021381:Protein Transport; D017382:Reactive Oxygen Species; D020744:rac GTP-Binding Proteins / Q000378:metabolism*; D020830:rac1 GTP-Binding Protein / Q000378:metabolism*
D019012:Integrin beta1; D009479:Neuropeptides; C107953:RAC1 protein, human; C484602:Rac1 protein, mouse; D017382:Reactive Oxygen Species; D019255:NADPH Oxidases; D019278:Matrix Metalloproteinase 3; D020744:rac GTP-Binding Proteins; D020830:rac1 GTP-Binding Protein