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 deposit extracellular matrix components, leaving behind a footprint that influences their crawling. Recent experiments showed that some 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 deposition 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 deposited footprint activates Rac1, a protein that establishes the cells front. Depending on footprint deposition rate and response to the footprint, cells on micropatterned lines can display many types of motility, including confined, oscillatory, and persistent motion. On two-dimensional substrates, we predict a transition between cells undergoing circular motion and cells developing an exploratory phenotype. Small quantitative changes in a cells interaction with its footprint can completely alter exploration, allowing cells to tightly regulate their motion, leading to different motility phenotypes (confined vs exploratory) in different cells when deposition 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. Significance StatementRecent experiments showed that epithelial cells modify and sense their local environment, creating a footprint that guides their own motion. Here, we explore how these deposited footprints regulate cell motility. We can recapitulate earlier experimental results with a model that assumes the footprint activates proteins that establish the cell front. We find that cells can use their footprints to change how they explore their surroundings, and that small changes in sensing or depositing footprint can switch the cell from being trapped to being able to explore new environments easily. We find both behaviors in experimental data, suggesting that cells can exhibit multiple crawling behaviors depending on how they deposit and respond to their foot-print.