title: Competition amongst Eph receptors regulates contact inhibition of locomotion and invasiveness in prostate cancer cells.
abstract: Metastatic cancer cells typically fail to halt migration on contact with non-cancer cells. This invasiveness is in contrast to normal mesenchymal cells that retract on contact with another cell. Why cancer cells are defective in contact inhibition of locomotion is not understood. Here, we analyse the dynamics of prostate cancer cell lines co-cultured with fibroblasts, and demonstrate that a combinatorial code of Eph receptor activation dictates whether cell migration will be contact inhibited. The unimpeded migration of metastatic PC-3 cells towards fibroblasts is dependent on activation of EphB3 and EphB4 by ephrin-B2, which we show activates Cdc42 and cell migration. Knockdown of EphB3 and EphB4 restores contact inhibition of locomotion to PC-3 cells. Conversely, homotypic collisions between two cancer cells results in contact inhibition of locomotion, mediated by EphA-Rho-Rho kinase (ROCK) signalling. Thus, the migration of cancer cells can switch from restrained to invasive, depending on the Eph-receptor profile of the cancer cell and the reciprocal ephrin ligands expressed by neighbouring cells.
authors.affiliation: School of Biochemistry, University of Bristol, Bristol, BS8 1TD, UK.
authors.forename: Jonathan W
authors.initials: JW
authors.lastname: Astin
authors.forename: Jennifer
authors.initials: J
authors.lastname: Batson
authors.forename: Shereen
authors.initials: S
authors.lastname: Kadir
authors.forename: Jessica
authors.initials: J
authors.lastname: Charlet
authors.forename: Raj A
authors.initials: RA
authors.lastname: Persad
authors.forename: David
authors.initials: D
authors.lastname: Gillatt
authors.forename: Jon D
authors.initials: JD
authors.lastname: Oxley
authors.forename: Catherine D
authors.initials: CD
authors.lastname: Nobes
mesh_terms: D002448:Cell Adhesion; D045744:Cell Line, Tumor; D002465:Cell Movement; D003260:Contact Inhibition; D042783:Endothelial Cells / Q000378:metabolism; D036388:Ephrin-B2 / Q000378:metabolism; D005347:Fibroblasts / Q000378:metabolism; D055785:Gene Knockdown Techniques; D006801:Humans; D008297:Male; D011471:Prostatic Neoplasms / Q000473:pathology*; D036081:Receptors, Eph Family / Q000378:metabolism*; D015398:Signal Transduction; D020764:cdc42 GTP-Binding Protein / Q000378:metabolism
chemical_list: D036388:Ephrin-B2; D036081:Receptors, Eph Family; D020764:cdc42 GTP-Binding Protein