Abstract
Directed cell migration in native environments is influenced by multiple migratory cues. These cues may include simultaneously occurring attractive soluble growth factor gradients and repulsive effects arising from cell-cell contact, termed contact inhibition of locomotion (CIL). How single cells reconcile potentially conflicting cues remains poorly understood. Here we show that a dynamic crosstalk between epidermal growth factor (EGF) mediated chemotaxis and CIL guide metastatic breast cancer cell motility, whereby cells become progressively insensitive to CIL in a chemotactic input-dependent manner. This balance is determined via integration of protrusion-enhancing signaling from EGF gradients and protrusion-suppressing signaling induced by CIL, mediated in part through EphB. Our results further suggest that EphB and EGF signaling inputs control protrusion formation by converging onto regulation of phosphatidylinositol 3-kinase (PI3K). We propose that this intricate interplay may enhance the spread of loose cell ensembles in pathophysiological conditions such as cancer, and possibly other physiological settings.
Highlights
Directed cell migration in native environments is influenced by multiple migratory cues
To quantitatively assay the effects of epidermal growth factor (EGF) gradients and to enhance the probability of cell–cell interactions leading to contact inhibition of locomotion (CIL), we developed a new microfluidic device based on previously developed device architectures[20,21], whereby gradients of soluble factors are generated across parallel arrays of cell-laden microchannels (Fig. 1a)
We found a significant difference between the repulsion probabilities of EphB3 knockdown and control cells (Fig. 5i); knockdown of the EphB3 receptor decreased the probability of repulsion when encountering ephrin-b1-fc-coated beads (Fig. 5i) to a level comparable to the probabilities observed for untreated MTLn3B1 cells encountering uncoated and fc-coated beads (Fig. 5d), while MTLn3-B1 cells treated with a control siRNA were repelled from ephrin-b1-fc-coated beads with a similar probability as untreated cells (Fig. 5i), supporting a role for EphB3 signalling in inducing CIL in MTLn3-B1 cells
Summary
Directed cell migration in native environments is influenced by multiple migratory cues These cues may include simultaneously occurring attractive soluble growth factor gradients and repulsive effects arising from cell–cell contact, termed contact inhibition of locomotion (CIL). Chemotaxis and CIL are generally recognized as important regulators of directed cell migration during metastasis, the interactions between these cues and how cancer cells integrate them are still poorly understood It is unclear how cells choose the direction of their migration in situations where different cues simultaneously act to specify opposing directions of motility and how the resulting decisions may affect the behaviour of the cell population. We suggest that the interplay between these cues can serve to switch between random and directed invasive cell migration, while serving as a more general paradigm for how other cellular systems resolve multiple cues
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