Determinants of leader cells in collective cell migration.

Collective migration is a basic mechanism of cell translocation during morphogenesis, wound repair and cancer invasion. Collective movement requires cells to retain cell-cell contacts, exhibit group polarization with defined front-rear asymmetry, and consequently move as one multicellular unit. Depending on the cell type, morphology of the group and the tissue context, distinct mechanisms control the leading edge dynamics and guidance. Leading edge migration may either result from adhesion to ECM and contractile pulling, or from forward pushing. The leading edge consists of either one or few dedicated tip cells or a multicellular leading row that generate adhesion and traction towards the tissue substrate. Alternatively, a multicellular bud consisting of many cells protrudes collectively by proliferation and growth thereby mechanically expanding and pushing towards the tissue stroma. Each type of collective guidance engages distinct spatiotemporal molecular control and feedback towards rearward cells and the adjacent tissue microenvironment; these include intrinsic polarity mechanisms regulated by the interplay between cell-cell and cell-ECM interactions; or the heterotypic integration of stromal cells that adopt leader cell functions. We here classify molecular and mechanical mechanisms of leading function in collective cell migration during morphogenesis and wound repair and discuss how these are recapitulated during collective invasion of cancer cells.