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

Oncogene volume 29, pages 4170–4182 (2010)Cite this article

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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.

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Acknowledgements

We acknowledge Fredrick Keeny in the Wistar Institute Microscopy Core for assistance with digital image processing and Ademi Santiago-Walker, PhD for critical review of the paper. This work is supported by grants from the NIH (NCI P01 CA098101 to M Herlyn, A Rustgi and D Basu), the Wistar Cancer Center Core Grant (P30 CA10815), and the American Cancer Society (IRG-78-002-30 to D Basu). This work is also supported in part with resources and use of facilities at the Philadelphia VA Medical Center.

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Authors and Affiliations

  1. Department of Otorhinolaryngology-Head and Neck Surgery, University of Pennsylvania, Philadelphia, PA, USA

    D Basu & G S Weinstein

  2. Veterans Administration Medical Center, Philadelphia, PA, USA

    D Basu

  3. The Wistar Institute, Philadelphia, PA, USA

    D Basu, T-T K Nguyen, G Zhang, J T Lee & M Herlyn

  4. Department of Pathology and Laboratory Medicine, University of Pennsylvania, Philadelphia, PA, USA

    K T Montone & L-P Wang

  5. Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA

    J A Diehl

  6. Department of Medicine, University of Pennsylvania, Philadelphia, PA, USA

    A K Rustgi

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  1. D Basu
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Correspondence to D Basu.

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Basu, D., Nguyen, TT., Montone, K. et al. Evidence for mesenchymal-like sub-populations within squamous cell carcinomas possessing chemoresistance and phenotypic plasticity. Oncogene 29, 4170–4182 (2010). https://doi.org/10.1038/onc.2010.170

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