Evidence for mesenchymal-like sub-populations within squamous cell carcinomas possessing chemoresistance and...

Area of Science:

• Oncology
• Cell Biology
• Cancer Research

Background:

• Tumor cell heterogeneity contributes to variable drug responses.
• Mesenchymal-like carcinoma cells exhibit resistance to chemotherapy and targeted therapies.

Purpose of the Study:

• To investigate the role of mesenchymal-like subpopulations in human squamous cell carcinomas (SCCs) regarding therapy resistance.
• To determine if these subpopulations contribute to resistance against conventional and epidermal growth factor receptor (EGFR)-targeted chemotherapy.

Main Methods:

• Identification and isolation of mesenchymal-like (Ecad-lo, high vimentin) subpopulations in SCC cell lines, xenografts, and clinical specimens.
• Assessment of cell turnover, paclitaxel resistance, and EGFR pathway signaling (MAPK, PI3K) in Ecad-lo cells.
• Evaluation of in vivo resistance to cetuximab, an EGFR-targeted antibody.

Main Results:

• A mesenchymal-like subset (Ecad-lo) with low E-cadherin and high vimentin was identified in SCCs.
• Ecad-lo cells exhibited lower cell turnover and resistance to paclitaxel.
• These cells showed diminished EGFR pathway stimulation and resistance to cetuximab due to lower EGFR expression.
• Phenotypic plasticity was observed, with dynamic interconversion between Ecad-lo and high E-cadherin states.

Conclusions:

• A distinct, low-turnover, mesenchymal-like subpopulation in SCCs possesses intrinsic resistance to conventional and EGFR-targeted chemotherapies.
• Reduced EGFR pathway function in this subpopulation underlies its resistance.
• Understanding this heterogeneity is crucial for developing more effective SCC treatment strategies.