title: Interplay between chemotaxis and contact inhibition of locomotion determines exploratory cell migration.
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.
authors: 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.
authors: Benjamin
authors: B
authors: Lin
authors: Department of Genetics and Developmental Biology, Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
authors: Taofei
authors: T
authors: Yin
authors: Department of Genetics and Developmental Biology, Center for Cell Analysis and Modeling, University of Connecticut Health Center, Farmington, Connecticut 06032, USA.
authors: Yi I
authors: YI
authors: Wu
authors: 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.|Precursory Research for Embryonic Science and Technology Investigator, Japan Science and Technology Agency, 4-1-8 Honcho Kawaguchi, Saitama 332-0012, Japan.
authors: Takanari
authors: T
authors: Inoue
authors: Department of Biomedical Engineering, School of Medicine, Johns Hopkins University, Baltimore, Maryland 21205, USA.|Department of Biomedical Engineering, Systems Biology Institute, Yale University, West Haven, Connecticut 06516, USA.
authors: Andre
authors: A
authors: Levchenko
mesh_terms: D000818:Animals; D015153:Blotting, Western; D045744:Cell Line, Tumor; D002465:Cell Movement / Q000235:genetics*; D002633:Chemotaxis / Q000235:genetics*; D003260:Contact Inhibition / Q000502:physiology*; D004815:Epidermal Growth Factor / Q000378:metabolism; D005260:Female; D055785:Gene Knockdown Techniques; D007091:Image Processing, Computer-Assisted; D007150:Immunohistochemistry; D015674:Mammary Neoplasms, Animal / Q000235:genetics* / Q000378:metabolism; D051381:Rats; D036223:Receptor, EphB3 / Q000235:genetics*; D036081:Receptors, Eph Family / Q000235:genetics; D020133:Reverse Transcriptase Polymerase Chain Reaction
chemical_list: D004815:Epidermal Growth Factor; D036223:Receptor, EphB3; D036081:Receptors, Eph Family