Elevated Src family kinase activity stabilizes E-cadherin-based junctions and collective movement of head and neck...

Area of Science:

• Oncology
• Cell Biology
• Molecular Medicine

Background:

• Epidermal Growth Factor Receptor (EGFR) overexpression is implicated in head and neck cancer, but EGFR-targeting therapies show limited efficacy.
• Alternative therapeutic targets are needed to improve outcomes in head and neck squamous cell carcinoma (HNSCC).
• Src family kinases (SFKs) are potential targets, often associated with tumor cell plasticity and loss of E-cadherin-mediated cell adhesion.

Purpose of the Study:

• To investigate the role of SFKs in head and neck carcinogenesis, particularly their relationship with E-cadherin and EGFR.
• To determine if SFKs contribute to tumor cell cohesion and invasion in HNSCC.
• To explore SFK inhibition as a potential therapeutic strategy for HNSCC.

Main Methods:

• Analysis of SFK expression and activation in advanced head and neck tumors (N=60) and HNSCC cell lines.
• Immunofluorescence to assess co-localization of Src and E-cadherin in cancer cells.
• Pharmacological inhibition of SFKs using SU6656 and genetic knockdown of Src/Yes.
• Assessment of E-cadherin localization and cellular junction integrity following SFK inhibition.

Main Results:

• Robust expression of total and activated Src was found in advanced HNSCC tumors and cell lines.
• Src co-localized with E-cadherin at cell-cell junctions, with constitutive Y419 phosphorylation independent of EGFR.
• Selective SFK inhibition with SU6656, or Src/Yes knockdown, disrupted cellular junctions and delocalized E-cadherin without altering its expression.
• These effects suggest an EGFR-independent role for SFKs in maintaining intercellular adhesion.

Conclusions:

• SFKs play a critical role in maintaining E-cadherin-based cell-cell junctions in HNSCC, independent of EGFR signaling.
• SFK activity contributes to the cohesive invasion of E-cadherin-positive HNSCC cells, a mechanism distinct from epithelial-mesenchymal transition.
• Targeting SFKs may offer a novel therapeutic approach to disrupt collective cell invasion in head and neck cancers.