Gradients in cell density and shape transitions drive collective cell migration into confining environments

Epithelial cell collectives migrate through tissue interfaces and crevices to orchestrate development processes, tumor invasion, and wound healing. Naturally, the traversal of cell collective through confining environments involves crowding due to narrowing spaces, which seems tenuous given the conventional inverse relationship between cell density and migration. However, the physical transitions required to overcome such epithelial densification for migration across confinements remain unclear. Here, in a system of contiguous microchannels of varying confinements, we show that epithelial (MCF10A) monolayers accumulate higher cell density and undergo fluid-like shape transitions before entering narrower channels. However, overexpression of breast cancer oncogene ErbB2 did not require such accumulation of cell density to migrate across matrix confinement. While wild-type MCF10A cells migrated faster in narrow channels, this confinement sensitivity was reduced after +ErbB2 mutation or with constitutively active RhoA. This physical interpretation of collective cell migration as density and shape transitions in granular matter could advance our understanding of complex living systems.