EVIDENCE FOR MESENCHYMAL-LIKE SUBPOPULATIONS WITHIN SQUAMOUS CELL CARCINOMAS POSSESSING CHEMORESISTANCE AND PHENOTYPIC PLASTICITY

Variable drug responses among malignant cells within individual tumors may represent a barrier to their eradication using chemotherapy. Carcinoma cells expressing mesenchymal markers resist conventional and epidermal growth factor receptor (EGFR)-targeted chemotherapy. Here we evaluated whether mesenchymal-like subpopulations within human squamous cell carcinomas (SCCs) with predominantly epithelial features contribute to overall therapy resistance. We identified a mesenchymal-like subset expressing low E-cadherin (Ecad-lo) and high vimentin (Vim-hi) within upper aerodigestive tract SCCs. This subset was both isolated from cell lines and identified in xenografts and primary clinical specimens. The Ecad-lo subset contained more low-turnover cells, correlating with resistance to the conventional chemotherapeutic paclitaxel in vitro. Epidermal growth factor (EGF) induced less stimulation of the MAP kinase and PI3-kinase pathways in Ecad-lo cells, which was likely due to lower EGFR expression in this subset and correlated with in vivo resistance to the EGFR-targeted antibody cetuximab. The Ecad-lo and high E-cadherin (Ecad-hi) subsets were dynamic in phenotype, showing the capacity to repopulate each other from single cell clones. Taken together, these results provide evidence for a low-turnover, mesenchymal-like subpopulation in SCCs with diminished EGFR pathway function and intrinsic resistance to conventional and EGFR-targeted chemotherapies.