Positive Quantitative Relationship between EMT and Contact-Initiated Sliding on 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, fiberlike micropatterns. We show here that low-dosage/short-duration exposure to transforming growth factor beta (TGFβ) induces partial EMT and enables sliding on narrower (26 μm) micropatterns than untreated counterparts (41 μm). 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 μm) micropatterns. These results identify a direct and quantitative relationship between EMT and cell sliding and show that EMT-associated invasive sliding is progressive, with cells that undergo partial EMT exhibiting intermediate sliding behavior and cells that transition more completely through EMT displaying maximal sliding. Our findings suggest a model in which fiber maturation and EMT work synergistically to promote invasiveness during cancer progression.