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The receptor tyrosine kinase Axl regulates cell–cell adhesion and stemness in cutaneous squamous cell carcinoma

Oncogene volume 33, pages 4185–4192 (2014)Cite this article

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Abstract

Axl is a receptor tyrosine kinase (RTK) upregulated in various tumors including cutaneous squamous cell carcinoma (SCC). Axl expression correlates with poor prognosis and induction of epithelial–mesenchymal transition (EMT), hence we hypothesized that Axl is involved in the disruption of cell–cell adhesion to allow invasion and chemotherapy resistance of the cancer stem cell population. Cutaneous SCC cell lines with stable knockdown of Axl were generated using retroviral vectors. Axl depletion altered expression of intercellular junction molecules increasing cell–cell adhesion with downregulation of Wnt and TGFβR signaling. Furthermore, Axl expression correlated with the expression of putative cancer stem cell markers, CD44 and ALDH1, increased resistance to chemotherapy drugs, enhanced sphere formation ability and expression of EMT features by cancer stem cells. Axl depletion resulted in loss of tumor formation in an in vivo zebrafish xenograft model. In conclusion, these data suggest that abrogation of Axl results in loss of cancer stem cell properties indicating a role for Axl as a therapeutic target in chemotherapy-resistant cancer.

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Acknowledgements

We are grateful to Carolyn Byrne for the luciferase reporter plasmids, Irene Leigh and Charlotte Proby for the MET1 and SCC IC1 cell lines and Vera Martins-Cabeços for scientific advice. We would like to acknowledge Alan Storey who was integral to the initiation of this project. This work was supported by a DAT PhD studentship from the Medical Research Council, a MRC Centenary award (MAC) and project grants from DEBRA Ireland and the British Skin Foundation awarded to EAOT.

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Authors and Affiliations

  1. Centre for Cutaneous Research, Blizard Institute, Barts and the London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    M A Cichoń, Z Szentpetery, M P Caley, I C Mackenzie & E A O'Toole

  2. Cancer Sciences Division, Cancer Research UK Centre, University of Southampton, Southampton, UK

    E S Papadakis

  3. School of Biological and Chemical Sciences, Queen Mary University of London, London, UK

    C H Brennan

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  1. M A Cichoń
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Correspondence to E A O'Toole.

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Cichoń, M., Szentpetery, Z., Caley, M. et al. The receptor tyrosine kinase Axl regulates cell–cell adhesion and stemness in cutaneous squamous cell carcinoma. Oncogene 33, 4185–4192 (2014). https://doi.org/10.1038/onc.2013.388

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