Polarizing cytoskeletal tension to induce leader cell formation during collective cell migration

The collective migration of cells is fundamental to epithelial biology. One of the hallmarks of collective behavior in migrating cohesive epithelial cell sheets is the emergence of so called leader cells. These cells exhibit a distinct morphology with a large and highly active lamellipodium. Although it is generally accepted that they play a crucial part in collective migration, the biophysical factors that regulate their formation remain unknown. Here we show that a geometry-based cue like local variation of curvature of the collective's perimeter is capable of triggering leader cell formation and promoting enhanced motility at defined positions. Remarkably, the extent of this effect scales with the magnitude of the curvature. Cytoskeletal tension was found to be important for geometry induced leader cell formation, as cells treated with tension reducing agents appeared less sensitive to local curvature variation. Accordingly, traction force microscopy revealed an increased level of shear stress at highly curved positions even before the cell migration had actually started, indicating the presence of a collective polarization induced by the geometry of the confinement. Together our findings suggest that high curvature leads to locally increased stress accumulation, mediated via cell-substrate interaction as well as via cytoskeleton tension. The stress accumulation in turn enhances the probability of leader cell formation as well as cell motility. This work defines the importance of geometric cue such as local curvature in the collective migration dynamics of epithelial cells and thus shows implications for the biophysical regulation of epithelium during wound healing, embryonic development, and oncogenesis.