EphB2 and ERK signaling are required for heterotypic contact inhibition of locomotion to drive cell sorting

Interactions between different cell-types can induce distinct contact inhibition of locomotion (CIL) responses that are hypothesized to control population-wide behaviors during embryogenesis. However, our understanding of the signals that lead to cell-type specific repulsion, and the precise capacity of heterotypic CIL responses to drive emergent behaviors is lacking. Using a new model of heterotypic CIL, we show that fibrosarcoma cells, but not fibroblasts, are actively repelled by epithelial cells in culture. We show that knocking down EphB2 or ERK in fibrosarcoma cells specifically leads to disruption of the repulsion phase of CIL in response to interactions with epithelial cells. We also examine the population-wide effects when these various cell combinations are allowed to interact in culture. Fibrosarcoma cells - unlike fibroblasts - completely segregate from epithelial cells, and inhibiting their distinct CIL response by knocking down EphB2 or ERK also disrupts this emergent sorting behavior. These data suggest that heterotypic CIL responses, in conjunction with processes such as differential adhesion, may aid the sorting of cell populations during embryogenesis.