Heterotypic intercellular adhesion tunes efficiency of cell-on-cell migration

Cell migration across epithelial barriers occurs in diverse developmental, immunological, and pathological contexts. Here we investigate the contribution of heterotypic adhesion between migrating cells and epithelial "substrate" cells to transepithelial migration. Using an in silico model inspired by the migration of primordial germ cells across the midgut epithelium in the Drosophila embryo, we show that heterotypic adhesion modulates migration efficiency in a non-monotonic manner, revealing the existence of an optimal adhesion regime. Consistent with this prediction, in vivo overexpression of E-cadherin in germ cells accelerated their exit from the midgut relative to controls. Beyond providing experimentally testable predictions, our model integrates and explains previous observations on the role of heterotypic adhesion in cell-on-cell migration, offering a framework for understanding transepithelial migration across biological contexts. Significance StatementCell adhesion is important for cell migration, and when cells migrate on a substrate of other cells (rather than on extracellular matrix), the adhesive properties of both cell types must be considered. However, whether and how dynamic changes in adhesion regulate cell-on-cell migration remains unclear. Here we approach this problem using transepithelial migration of Drosophila embryonic germ cells as a case study. We develop an in silico model of the migration process that predicts an optimal level of adhesion between migrating cell and substrate cell to achieve efficient migration. In vivo live imaging and genetic manipulation experiments uphold the predictions of this model. This suggests that adhesion is not a simple on/off binary parameter regulating migration.