Diversity in cell migration strategies. In the tissue microenvironment, different cell types exhibit distinct migration strategies. (A) Mesenchymal migration: Mesenchymal cells display an adhesive phenotype and develop a spindle shape. The elongated morphology is dependent on integrin-mediated adhesion and the presence of traction forces on both cell poles. Simultaneous with integrin and actin concentration at focal contacts, the cells recruit surface proteases to these substrate contact sites to digest and remodel the extracellular matrix, thus generating matrix defects that allow cell migration. Other cells may follow along the generated matrix defect creating a moving cell chain. (B) Cluster/cohort migration: Migrating cancer cell collectives use an integrin- and protease-dependent migration mode similar to mesenchymal migration, but the migrating cells within the cohorts are interconnected by cadherins and gap-junctional communication. (C) Ameboid migration: Lymphoid cells display a characteristic “ameboid” type of migration, in which integrin-mediated adhesion is dispensable and cell movement is driven by short-lived relatively weak interactions with the substrate. The lack of focal contacts and high deformability of lymphocytes allow movement at high velocity, while the fast deformability of lymphocytes allows them to overcome matrix barriers by physical mechanisms, independent of proteolytic matrix degradation.⁶