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Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy

Oncogene volume 36, pages 667–677 (2017)Cite this article

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Abstract

The transdifferentiation of epithelial cells toward a mesenchymal condition (EMT) is a complex process that allows tumor cells to migrate to ectopic sites. Cadherins are not just structural proteins, but they act as sensors of the surrounding microenvironment and as signaling centers for cellular pathways. However, the molecular mechanisms underlying these signaling functions remain poorly characterized. Cadherin-6 (CDH6) is a type 2 cadherin, which drives EMT during embryonic development and it is aberrantly re-activated in cancer. We recently showed that CDH6 is a TGFβ target and an EMT marker in thyroid cancer, suggesting a role for this protein in the progression of this type of tumor. Papillary thyroid carcinomas (PTCs) are usually indolent lesions. However, metastatic spreading occurs in about 5% of the cases. The identification of molecular markers that could early predict the metastatic potential of these lesions would be strategic to design more tailored approaches and reduce patients overtreatment. In this work, we assessed the role of CDH6 in the metastatic progression of thyroid cancer. We showed that loss of CDH6 expression profoundly changes cellular architecture, alters the inter-cellular interaction modalities and attenuates EMT features in thyroid cancer cells. Using a yeast two-hybrid screening approach, based on a thyroid cancer patients library, we showed that CDH6 directly interacts with GABARAP, BNIP3 and BNIP3L, and that through these interactions CDH6 restrains autophagy and promotes re-organization of mitochondrial network through a DRP1-mediated mechanism. Analysis of the LIR domains suggests that the interaction with the autophagic machinery may be a common feature of many cadherin family members. Finally, the analysis of CDH6 expression in a unique cohort of human PTCs showed that CDH6 expression marks specifically EMT cells. and it is strongly associated with metastatic behavior and worse outcome of PTCs.

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Acknowledgements

Additional Materials and Methods are supplied in the Supplementary Information. This work was supported by the Italian Association for Cancer Research (AIRC, MFAG10745) and by the Italian Ministry of Health (GR-2011-02350937). GG is supported by a fellowship of the Umberto Veronesi Foundation.

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Author notes

  1. M Gugnoni and V Sancisi: These authors contributed equally to this work.

Authors and Affiliations

  1. Department of Scientific Direction, Laboratory of Translational Research, Arcispedale S Maria Nuova-IRCCS, Reggio Emilia, Italy

    M Gugnoni, V Sancisi, G Gandolfi, G Manzotti, M Tigano & A Ciarrocchi

  2. Pathology Unit, Deptartment of Oncology and Advanced Technologies, Arcispedale S Maria Nuova-IRCCS, Reggio Emilia, Italy

    M Ragazzi, I Tamagnini & S Piana

  3. Department of General Surgery and Specialistic Unit, Otolaryngology Unit, Arcispedale S Maria Nuova-IRCCS, Reggio Emilia, Italy

    D Giordano

  4. Department of General Surgery and Specialistic Unit, Endocrinology Unit, Arcispedale S Maria Nuova-IRCCS, Reggio Emilia, Italy

    A Frasoldati

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Gugnoni, M., Sancisi, V., Gandolfi, G. et al. Cadherin-6 promotes EMT and cancer metastasis by restraining autophagy. Oncogene 36, 667–677 (2017). https://doi.org/10.1038/onc.2016.237

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