Mechanical adaptability of cell migration in 3D collagen gels

Migration of cells across tissues with diverse biophysical environments plays a crucial role in a wide variety of physiological functions and pathological processes, such as in embryonic development, wound healing, haemostasis, tumor and cancer progression. Indeed, one of the most devastating features of cancer is metastasis_the ability of cancer cells to escape from the primary tumor and invade and colonize a distant tissue. Understanding the biophysical and biochemical mechanisms underlying cell migration remains a challenge, however, partly because it has been only recently realized that cells employ different strategies and molecular mechanisms in three-dimensional (3D) environments, compared to on traditional 2D glass surfaces. In this work, we examined cell migration, simultaneously at the individual cell and cell population levels, in a 3D collagen hydrogel model mimicking the connective tissue topology confronted by malignant breast cancer cells. Our findings revealed two distinct migration patterns that depend specifically on the location of the individual cells within the population: a rapid and directionally persistent migration of the “leader cells” and a more randomized migration of the “follower cells”. This disparity, strikingly, occurred with minimal cell-cell contacts. Rather, this heterogeneity is associated with local remodeling of the pericellular matrix and results in an apparent independence of the inherent migration on matrix condition. Despite such robustness, effects of anti-migratory drugs were interestingly observed to vary strongly with matrix stiffness and architecture. Specifically, cytoskeletal contractility-targeting drugs reduced migration speed in sparse gels, whereas migration in dense gels was retarded effectively by inhibiting proteolysis. Our results therefore corroborate a mechanistic plasticity that allows cells to actively adapt their invasion machinery depending on the local biophysical microenvironment