Neighbor-enhanced diffusivity in dense, cohesive cell populations

The dispersal or mixing of cells within cellular tissue is a crucial property for diverse biological processes, ranging from morphogenesis, immune action, to tumor metastasis. With the phenomenon of ‘contact inhibition of locomotion,’ it is puzzling how cells achieve such processes within a densely packed cohesive population. Here we demonstrate that a proper degree of cell-cell adhesiveness can, intriguingly, enhance the super-diffusive nature of individual cells. We systematically characterize the migration trajectories of crawling MDA-MB-231 cell lines, while they are in several different clustering modes, including freely crawling singles, cohesive doublets of two cells, quadruplets, and confluent population on two-dimensional substrate. Following data analysis and computer simulation of a simple cellular Potts model, which faithfully recapitulated all key experimental observations such as enhanced diffusivity as well as periodic rotation of cell-doublets and cell-quadruplets with mixing events, we found that proper combination of active self-propelling force and cell-cell adhesion is sufficient for generating the observed phenomena. Additionally, we found that tuning parameters for these two factors covers a variety of different collective dynamic states.Author summary: Dispersal or movement of cells within dense biological tissue is essential for diverse biological processes, ranging from pattern formation, immune action, to tumor metastasis. However, it is quite puzzling how cells acquire such ability when they are supposedly “caged” by neighboring cells. Here, we report an unusual property of (MDA-MB-231) breast cancer cells that diffuse more persistently within a densely packed population than when they are free to crawl around with little interference. This property is rather surprising since they prefer to stick together, forming clusters. Interestingly, however, we find that having sticky neighbors not only makes two active cells in contact periodically rotate, reminiscent of a ballroom dance, but also enhances the persistence of the cells within a dense population. These intriguing phenomena appear to be universal as they can be generated by a simple cellular Potts model with appropriate combination of active self-propulsion and cell-cell adhesion force.