Extent of EMT promotes invasive, contact-induced sliding on progressively narrower fiber-like tracks

Abstract

Epithelial-mesenchymal transition (EMT) is a complex process by which cells acquire invasive properties that enable escape from the primary tumor. Complete EMT, however, is not required for metastasis: circulating tumor cells exhibit hybrid epithelial-mesenchymal states, and genetic perturbations promoting partial EMT induce metastasis in vivo. An open question is whether and to what extent intermediate stages of EMT promote invasiveness. Here, we investigate this question, building on recent observation of a new invasive property. Migrating cancer cell lines and cells transduced with prometastatic genes slide around other cells on spatially-confined, fiber-like micropatterns. We show here that low-dosage/short-duration exposure to TGF{beta} induces partial EMT and enables sliding on narrower (26 {micro}m) micropatterns than untreated counterparts (41 {micro}m). High-dosage/long-duration exposure induces more complete EMT, including disrupted cell-cell contacts and reduced E-cadherin expression, and promotes sliding on the narrowest (15 {micro}m) micropatterns. These results demonstrate that EMT is a potent inducer of cell sliding, even under significant spatial constraints, and EMT-mediated invasive sliding is progressive, with partial EMT promoting intermediate sliding behavior. Our findings suggest a model in which fiber maturation and partial EMT work synergistically to promote invasiveness during cancer progression.