Abstract C77: A mesenchymal-like subpopulation within squamous cell carcinomas with chemotherapy resistance and phenotypic plasticity

Abstract

A major barrier to curative therapy for most malignancies is intrinsic drug resistance within discrete tumor cell subpopulations, which are presently ill-defined. Previous studies show that carcinoma cell lines abundantly expressing mesenchymal markers have increased resistance to both conventional chemotherapy and epidermal growth factor receptor (EGFR)-targeted agents. However it is unclear whether small mesenchymal-like subpopulations contribute to therapy resistance in individual carcinomas with predominantly epithelial features. Here we identified a mesenchymallike subset expressing low E-cadherin (Ecad lo) and high vimentin (Vim hi) within human squamous cell carcinomas of the esophagus (ESCC) and head and neck (HNSCC). This minority subset was readily isolated from two HNSCC lines (SCC9 and OCTT2) and was identifiable in vivo, not only in mouse xenografts of these lines but also in the clinical specimen from which a HNSCC cell line (OCTT2) was derived. The minority Ecad lo/Vim hi subset contained more low-turnover cells and was less proliferative overall, correlating with increased resistance to the conventional chemotherapeutic agent paclitaxel. The Ecad lo/Vim hi subpopulation also demonstrated diminished activity in the MAP kinase/PI3-kinase pathways, likely arising from decreased EGFR expression and correlating with increased in vitro resistance to the EGFR-targeted agent, cetuximab. This mesenchymal-like subpopulation displayed comparable drug resistancein vivo, becoming enriched by cetuximab treatment in a mouse xenograft derived directly from a clinical HNSCC specimen. Furthermore, the Ecad lo/Vim hi and Ecad hi/Vim lo subsets were dynamic and reversible in their phenotypes, showing the capacity to repopulate each other from single cell clones. Taken together, these results show that a low-turnover, mesenchymal-like subpopulation in squamous cell carcinomas has diminished EGFR pathway function and elevated intrinsic resistance to both conventional and targeted chemotherapies. They further suggest that this mesenchymal-like subset retains the plasticity to repopulate other malignant subpopulations post therapy. Citation Information: Cancer Res 2009;69(23 Suppl):C77.