Figure 2.

The ‘nuts and bolts’ of endocytic-mediated jamming transition, and its biological consequences. (1) Global perturbations of endosomal function through elevation of the master regulator of early endosomes, RAB5A, alter endosomal numbers and macropinocytic internalization [61]. (2a–c) These alterations, in turn, can cause: increased turnover of junctional proteins (e.g. E-cadherin) and junctional tension (2a); greater volume and density fluctuations, as hallmarks of liquid-to-solid-like transition (2b); and increased formation of RAC1-dependent, polarized protrusions that can extend beneath neighbouring cells (also called cryptic lamellipodia), which promotes cell self-propulsion (2c). (3) The combination of these cellular and mechanical alterations influences the kinematics of epithelial monolayers, which can be understood through mathematical modelling. The simulation is based on a self-propelled Voronoi model with two main components: the target shape of each individual cell (p₀, ratio between perimeter and square-root of the area), which is the result of competition between intracellular adhesion and cortical tension [61]; and the inverse of the reorientation time that each individual cell takes to align to the local direction of motion, τ⁻¹. These components generate a phase diagram (bottom left) that explains endocytic re-awakening of movement in jammed epithelia, in terms of a combination of large-scale directed migration in the presence of local cell re-arrangement, which lead to a ‘flocking’ (or flowing) liquid mode of migration. (4) This transition in the mode of movement enables RAB5A-expressing epithelial monolayers to flow through micro-fabricated narrow slits that mimic the confined channels encountered during interstitial migration. (5) This might promote mechanosensitive programmes, such as the YAP1/TAZ axis [65], for the acquisition of metastatic traits. Adapted from [66], copyright (2018), with permission from Elsevier.