Secreted footprints let cells switch between confined, oscillatory, and exploratory migration.

For eukaryotic cells to heal wounds, respond to immune signals, or metastasize, they must migrate, often by adhering to extracellular matrix. Cells may also secrete matrix factors, leaving behind a footprint that influences their crawling. Recent experiments showed that epithelial cells on micropatterned adhesive stripes move persistently in regions they have previously crawled over, where footprints have been formed, but barely advance into unexplored regions, creating an oscillatory migration of increasing amplitude. Here, we explore through mathematical modeling how footprint secretion and cell responses to footprint combine to allow cells to develop oscillation and other complex migratory motions. We simulate cell crawling with a phase field model coupled to a biochemical model of cell polarity, assuming local contact with the secreted footprint activates Rac1, a polarity protein at the front of the cell. Depending on the footprint secretion rate and the response to the footprint, cells on micropatterned lines can display a variety of types of motility, including confined, oscillatory, and persistent motion. On 2D substrates, we predict a transition between cells undergoing circular motion and cells developing a more exploratory phenotype. Our model shows how minor changes in a cell's interaction with its footprint can completely alter exploration, allowing cells to tightly regulate their motion, as well as leading to a wide spectrum of behaviors when secretion or sensing is variable from cell to cell. Consistent with our computational predictions, we find in earlier experimental data evidence of cells undergoing both circular and exploratory motion. Our work proposes a new paradigm for how cells regulate their own motility.