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

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

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 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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Blotting, Western
  • Cell Line, Tumor
  • Cell Movement / genetics*
  • Chemotaxis / genetics*
  • Contact Inhibition / physiology*
  • Epidermal Growth Factor / metabolism
  • Female
  • Gene Knockdown Techniques
  • Image Processing, Computer-Assisted
  • Immunohistochemistry
  • Mammary Neoplasms, Animal / genetics*
  • Mammary Neoplasms, Animal / metabolism
  • Rats
  • Receptor, EphB3 / genetics*
  • Receptors, Eph Family / genetics
  • Reverse Transcriptase Polymerase Chain Reaction

Substances

  • Epidermal Growth Factor
  • Receptor, EphB3
  • Receptors, Eph Family