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Controversies around epithelial–mesenchymal plasticity in cancer metastasis

Nature Reviews Cancer volume 19, pages 716–732 (2019)Cite this article

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Abstract

Experimental evidence accumulated over decades has implicated epithelial–mesenchymal plasticity (EMP), which collectively encompasses epithelial–mesenchymal transition and the reverse process of mesenchymal–epithelial transition, in tumour metastasis, cancer stem cell generation and maintenance, and therapeutic resistance. However, the dynamic nature of EMP processes, the apparent need to reverse mesenchymal changes for the development of macrometastases and the likelihood that only minor cancer cell subpopulations exhibit EMP at any one time have made such evidence difficult to accrue in the clinical setting. In this Perspectives article, we outline the existing preclinical and clinical evidence for EMP and reflect on recent controversies, including the failure of initial lineage-tracing experiments to confirm a major role for EMP in dissemination, and discuss accumulating data suggesting that epithelial features and/or a hybrid epithelial–mesenchymal phenotype are important in metastasis. We also highlight strategies to address the complexities of therapeutically targeting the EMP process that give consideration to its spatially and temporally divergent roles in metastasis, with the view that this will yield a potent and broad class of therapeutic agents.

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Fig. 1: Types of EMP stimuli.
Fig. 2: Therapy-induced EMT and potential EMT-suppressing regimens.
Fig. 3: Therapeutic opportunities to address EMP.

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Change history

  • 08 November 2019

    The article was updated to add the ORCID ID for Elizabeth D. Williams.

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Acknowledgements

The authors acknowledge research support in the form of funding from the Australian Government Department of Health (Australian Prostate Cancer Centre – Queensland), Movember Foundation and the Prostate Cancer Foundation of Australia through a Movember Revolutionary Team Award (E.D.W.), Princess Alexandra Research Foundation (E.D.W, E.W.T.), National Breast Cancer Foundation (E.W.T.), the Australia India Council (E.W.T.), NIH (5R01CA205418; D.G.) and The Neuberger Berman Foundation Lung Cancer Research Center at Weill Cornell Medicine (D.G.). The Translational Research Institute receives funding from the Australian Government.

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Authors and Affiliations

  1. Institute of Health and Biomedical Innovation and School of Biomedical Sciences, Queensland University of Technology (QUT), Brisbane, Queensland, Australia

    Elizabeth D. Williams & Erik W. Thompson

  2. Translational Research Institute (TRI), Brisbane, Queensland, Australia

    Elizabeth D. Williams & Erik W. Thompson

  3. Australian Prostate Cancer Research Centre – Queensland (APCRC-Q) and Queensland Bladder Cancer Initiative (QBCI), Brisbane, Queensland, Australia

    Elizabeth D. Williams

  4. Department of Cardiothoracic Surgery, Department of Cell and Developmental Biology and Neuberger Berman Lung Cancer Center, Weill Cornell Medicine, New York, NY, USA

    Dingcheng Gao

  5. Department of Medicine, School of Medicine, University of Western Australia, Fiona Stanley Hospital Campus, Perth, Western Australia, Australia

    Andrew Redfern

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Williams, E.D., Gao, D., Redfern, A. et al. Controversies around epithelial–mesenchymal plasticity in cancer metastasis. Nat Rev Cancer 19, 716–732 (2019). https://doi.org/10.1038/s41568-019-0213-x

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