title: Elevated Src family kinase activity stabilizes E-cadherin-based junctions and collective movement of head and neck squamous cell carcinomas.
abstract: EGF receptor (EGFR) overexpression is thought to drive head and neck carcinogenesis however clinical responses to EGFR-targeting agents have been modest and alternate targets are actively sought to improve results. Src family kinases (SFKs), reported to act downstream of EGFR are among the alternative targets for which increased expression or activity in epithelial tumors is commonly associated to the dissolution of E-cadherin-based junctions and acquisition of a mesenchymal-like phenotype. Robust expression of total and activated Src was observed in advanced stage head and neck tumors (N=60) and in head and neck squamous cell carcinoma lines. In cultured cancer cells Src co-localized with E-cadherin in cell-cell junctions and its phosphorylation on Y419 was both constitutive and independent of EGFR activation. Selective inhibition of SFKs with SU6656 delocalized E-cadherin and disrupted cellular junctions without affecting E-cadherin expression and this effect was phenocopied by knockdown of Src or Yes. These findings reveal an EGFR-independent role for SFKs in the maintenance of intercellular junctions, which likely contributes to the cohesive invasion E-cadherin-positive cells in advanced tumors. Further, they highlight the need for a deeper comprehension of molecular pathways that drive collective cell invasion, in absence of mesenchymal transition, in order to combat tumor spread.
authors.affiliation: University of Nice Sophia Antipolis, UFR Sciences, Nice, France.|CNRS, UMR7277, Nice, France.|Inserm, U1091, Nice, France.
authors.forename: Laurence
authors.initials: L
authors.lastname: Veracini
authors.affiliation: University of Nice Sophia Antipolis, UFR Sciences, Nice, France.|CNRS, UMR7277, Nice, France.|Inserm, U1091, Nice, France.
authors.forename: Dominique
authors.initials: D
authors.lastname: Grall
authors.affiliation: University of Nice Sophia Antipolis, UFR Sciences, Nice, France.|CNRS, UMR7277, Nice, France.|Inserm, U1091, Nice, France.
authors.forename: Sébastien
authors.initials: S
authors.lastname: Schaub
authors.affiliation: University of Nice Sophia Antipolis, UFR Sciences, Nice, France.|CNRS, UMR7277, Nice, France.|Inserm, U1091, Nice, France.|Department of Pathology, Centre Antoine Lacassagne, Nice, France.
authors.forename: Stéphanie
authors.initials: S
authors.lastname: Beghelli-de la Forest Divonne
authors.affiliation: Laboratory of Oncopharmacology, Centre Antoine Lacassagne, Nice, France.
authors.forename: Marie-Christine
authors.initials: MC
authors.lastname: Etienne-Grimaldi
authors.affiliation: Laboratory of Oncopharmacology, Centre Antoine Lacassagne, Nice, France.
authors.forename: Gérard
authors.initials: G
authors.lastname: Milano
authors.affiliation: Department of Otorhinolaryngology, Centre Antoine Lacassagne, Nice, France.
authors.forename: Alexandre
authors.initials: A
authors.lastname: Bozec
authors.affiliation: Department of Otorhinolaryngology and Cervicofacial Surgery, CHU, Caen, France.
authors.forename: Emmanuel
authors.initials: E
authors.lastname: Babin
authors.affiliation: Department of Pathology, Centre Antoine Lacassagne, Nice, France.
authors.forename: Anne
authors.initials: A
authors.lastname: Sudaka
authors.affiliation: University of Nice Sophia Antipolis, UFR Sciences, Nice, France.|CNRS, UMR7277, Nice, France.|Inserm, U1091, Nice, France.|Laboratory of Oncopharmacology, Centre Antoine Lacassagne, Nice, France.
authors.forename: Juliette
authors.initials: J
authors.lastname: Thariat
authors.affiliation: University of Nice Sophia Antipolis, UFR Sciences, Nice, France.|CNRS, UMR7277, Nice, France.|Inserm, U1091, Nice, France.|Department of Pathology, Centre Antoine Lacassagne, Nice, France.
authors.forename: Ellen
authors.initials: E
authors.lastname: Van Obberghen-Schilling
mesh_terms: D015820:Cadherins / Q000378:metabolism*; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D006258:Head and Neck Neoplasms / Q000235:genetics* / Q000473:pathology; D006801:Humans; D015398:Signal Transduction; D019061:src-Family Kinases / Q000378:metabolism*
chemical_list: D015820:Cadherins; D019061:src-Family Kinases
keywords: E-cadherin; Src kinases; collective migration; head and neck cancer