Elevated Src family kinase activity stabilizes E-cadherin-based junctions and collective movement of head and neck squamous cell carcinomas
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Laurence Veracini1,2,3, Dominique Grall1,2,3, Sébastien Schaub1,2,3, Stéphanie Beghelli-de la Forest Divonne1,2,3,4, Marie-Christine Etienne-Grimaldi5, Gérard Milano5, Alexandre Bozec6, Emmanuel Babin7, Anne Sudaka4, Juliette Thariat1,2,3,5 and Ellen Van Obberghen-Schilling1,2,3,4
1 University of Nice Sophia Antipolis, UFR Sciences, Nice, France
2 CNRS, UMR7277, Nice, France
3 Inserm, U1091, Nice, France
4 Department of Pathology, Centre Antoine Lacassagne, Nice, France
5 Laboratory of Oncopharmacology, Centre Antoine Lacassagne, Nice, France
6 Department of Otorhinolaryngology, Centre Antoine Lacassagne, Nice, France
7 Department of Otorhinolaryngology and Cervicofacial Surgery, CHU, Caen, France
Ellen Van Obberghen-Schilling, email:
Keywords: Head and neck cancer, Src kinases, E-cadherin, collective migration
Received: September 25, 2014 Accepted: December 23, 2014 Published: December 26, 2014
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.
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