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Nat Commun. 2015 Apr 8;6:6619. doi: 10.1038/ncomms7619.

Interplay between chemotaxis and contact inhibition of locomotion determines exploratory cell migration.

Lin B1,2,3, Yin T4, Wu YI4, Inoue T1,2,5, Levchenko A1,3.

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Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Department of Cell Biology, Center for Cell Dynamics, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.
Department of Biomedical Engineering, Systems Biology Institute, Yale University, West Haven, Connecticut 06516, USA.
Department of Genetics and Developmental Biology, Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
Precursory Research for Embryonic Science and Technology Investigator, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.


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 guides 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 signalling from EGF gradients and protrusion-suppressing signalling induced by CIL, mediated in part through EphB. Our results further suggest that EphB and EGF signalling 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.

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