Multiscale obstruction sensitivity in collective cell migration

Abstract

Cellular forces and intercellular cooperation generate collective cell migration. Pathological changes in cell-level genetic and physical properties cause jamming, unjamming, and scattering in epithelial migration. Separately, changes in microenvironment stiffness and confinement can produce varying modes of cell migration. However, it remains unclear whether and how mesoscale disruptions in matrix topology alter collective cell migration. To address this question, we microfabricated matrices with stumps of defined geometry, density, and orientation, which serve as obstructions in the path of collectively migrating healthy mammary epithelial cells. Here, we show that cells lose their speed and directionality when moving through dense obstructions, compared to those sparsely spaced. On flat surfaces, leader cells are significantly stiffer than follower cells, while dense obstructions lead to the overall softening of cells. In moving through dense obstructions, epithelial cells lose the sense of leaders and followers in their physical properties, migration phenotypes, and fluidity. Although Rac inhibition reduces obstruction sensitivity, loss of cell-cell cooperation and induction of leader-like phenotype via -catenin depletion eliminates the effect of matrix obstructions on epithelial migration. Through a lattice-based model, we identify cellular protrusions, polarity, and leader-follower communication as key mechanisms for obstruction-sensitive collective cell migration. Together, microscale cytoskeletal response, mesoscale softening and disorder, and macroscale multicellular communication enable epithelial cell populations to sense topological obstructions encountered in challenging environments. These results reveal that cohesive, healthy populations are more obstruction sensitive than the dysfunctional, aggressive ones. The obstruction-sensitivity could add to the emerging disease mechanotypes such as cell stiffness and traction forces.