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Interconnected high-dimensional landscapes of epithelial–mesenchymal plasticity and stemness in cancer

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Abstract

Establishing macrometastases at distant organs is a highly challenging process for cancer cells, with extremely high attrition rates. A very small percentage of disseminated cells have the ability to dynamically adapt to their changing micro-environments through reversibly switching to another phenotype, aiding metastasis. Such plasticity can be exhibited along one or more axes—epithelial–mesenchymal plasticity (EMP) and cancer stem cells (CSCs) being the two most studied, and often tacitly assumed to be synonymous. Here, we review the emerging concepts related to EMP and CSCs across multiple cancers. Both processes are multi-dimensional in nature; for instance, EMP can be defined on morphological, molecular and functional changes, which may or may not be synchronized. Similarly, self-renewal, multi-lineage potential, and resistance to anoikis and/or therapy may not all occur simultaneously in CSCs. Thus, understanding the complexity in defining EMP and CSCs is essential if we are to understand their contribution to cancer metastasis. This will require a more comprehensive understanding of the non-linearity of these processes. These processes are dynamic, reversible, and semi-independent in nature; cells traverse the inter-connected high-dimensional EMP and CSC landscapes in diverse paths, each of which may exhibit a distinct EMP-CSC coupling. Our proposed model offers a potential unifying framework for elucidating the coupled decision-making along these dimensions and highlights a key set of open questions to be answered.

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Acknowledgements

MKJ was supported by Ramanujan Fellowship (SB/S2/RJN-049/2018) awarded by Science and Engineering Research Board, Department of Science and Technology, Government of India; and by InfoSys Foundation, Bangalore. ASD acknowledges support from Prime Ministers’ Research Fellowship (PMRF). AB is supported by Animal Free Research UK.

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Authors and Affiliations

  1. Centre for BioSystems Science and Engineering (BSSE), Indian Institute of Science, Bangalore, 560012, India

    Sarthak Sahoo, Atchuta Srinivas Duddu & Mohit Kumar Jolly

  2. UG Programme, Indian Institute of Science, Bangalore, 560012, India

    Sarthak Sahoo

  3. Department of Biotechnology, Central University of Kashmir, Ganderbal, India

    Bazella Ashraf

  4. Blizard Institute, Barts and The London School of Medicine and Dentistry, Queen Mary University of London, London, UK

    Adrian Biddle

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  1. Sarthak Sahoo
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  2. Bazella Ashraf
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  3. Atchuta Srinivas Duddu
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  4. Adrian Biddle
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  5. Mohit Kumar Jolly
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MKJ and AB conceptualized and edited the review; SS, BA and ASD prepared the first version and associated artwork. All authors contributed to writing the manuscript.

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Sahoo, S., Ashraf, B., Duddu, A.S. et al. Interconnected high-dimensional landscapes of epithelial–mesenchymal plasticity and stemness in cancer. Clin Exp Metastasis 39, 279–290 (2022). https://doi.org/10.1007/s10585-021-10139-2

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