title: Evidence for mesenchymal-like sub-populations within squamous cell carcinomas possessing chemoresistance and phenotypic plasticity.
abstract: 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. In this study, we evaluated whether mesenchymal-like sub-populations 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 within the upper aerodigestive tract SCCs. This subset was both isolated from the cell lines and was 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 induced less stimulation of the mitogen-activated protein kinase and phosphatidylinositol-3-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 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 sub-population in SCCs with diminished EGFR pathway function and intrinsic resistance to conventional and EGFR-targeted chemotherapies.
authors.affiliation: Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA 19104, USA. devraj.basu@uphs.upenn.edu
authors.forename: D
authors.initials: D
authors.lastname: Basu
authors.forename: T-T K
authors.initials: TT
authors.lastname: Nguyen
authors.forename: K T
authors.initials: KT
authors.lastname: Montone
authors.forename: G
authors.initials: G
authors.lastname: Zhang
authors.forename: L-P
authors.initials: LP
authors.lastname: Wang
authors.forename: J A
authors.initials: JA
authors.lastname: Diehl
authors.forename: A K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: J T
authors.initials: JT
authors.lastname: Lee
authors.forename: G S
authors.initials: GS
authors.lastname: Weinstein
authors.forename: M
authors.initials: M
authors.lastname: Herlyn
mesh_terms: D000911:Antibodies, Monoclonal / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy / Q000473:pathology*; D045744:Cell Line, Tumor; D000068818:Cetuximab; D019008:Drug Resistance, Neoplasm; D006801:Humans; D020935:MAP Kinase Signaling System; D008648:Mesoderm / Q000473:pathology*; D017239:Paclitaxel / Q000494:pharmacology; D010641:Phenotype; D019869:Phosphatidylinositol 3-Kinases / Q000502:physiology
chemical_list: D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D019869:Phosphatidylinositol 3-Kinases; D017239:Paclitaxel; D000068818:Cetuximab