Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer

  1. Andrea Sacchetti
  2. Miriam Teeuwssen
  3. Mathijs Verhagen
  4. Rosalie Joosten
  5. Tong Xu
  6. Roberto Stabile
  7. Berdine van der Steen
  8. Martin M Watson
  9. Alem Gusinac
  10. Won Kyu Kim
  11. Inge Ubink
  12. Harmen JG Van de Werken
  13. Arianna Fumagalli
  14. Madelon Paauwe
  15. Jacco Van Rheenen
  16. Owen J Sansom
  17. Onno Kranenburg
  18. Riccardo Fodde  Is a corresponding author
  1. Erasmus MC, Netherlands
  2. Korea Institute of Science and Technology, Republic of Korea
  3. University Medical Centre Utrecht, Netherlands
  4. Princess Máxima Center for Pediatric Oncology, Netherlands
  5. Cancer Research UK Beatson Institute, United Kingdom
  6. Netherlands Cancer Institute, Netherlands
  7. CRUK Beatson Institute, United Kingdom

Abstract

Phenotypic plasticity represents the most relevant hallmark of the carcinoma cell as it bestows it with the capacity of transiently altering its morphologic and functional features while en route to the metastatic site. However, the study of phenotypic plasticity is hindered by the rarity of these events within primary lesions and by the lack of experimental models. Here, we identified a subpopulation of phenotypic plastic colon cancer cells: EpCAMlo cells are motile, invasive, chemo-resistant, and highly metastatic. EpCAMlo bulk and single-cell RNAseq analysis indicated 1. enhanced Wnt/b-catenin signaling, 2. a broad spectrum of degrees of EMT activation including hybrid E/M states (partial EMT) with highly plastic features, and 3. high correlation with the CMS4 subtype, accounting for colon cancer cases with poor prognosis and a pronounced stromal component. Of note, a signature of genes specifically expressed in EpCAMlo cancer cells is highly predictive of overall survival in tumors other than CMS4, thus highlighting the relevance of quasi-mesenchymal tumor cells across the spectrum of colon cancers. Enhanced Wnt and the downstream EMT activation represent key events in eliciting phenotypic plasticity along the invasive front of primary colon carcinomas. Distinct sets of epithelial and mesenchymal genes define transcriptional trajectories through which state transitions arise. pEMT cells, often earmarked by the extracellular matrix glycoprotein SPARC together with nuclear ZEB1 and b-catenin along the invasive front of primary colon carcinomas, are predicted to represent the origin of these (de)differentiation routes through biologically-distinct cellular states, and to underlie the phenotypic plasticity of colon cancer cells.

Data availability

The RNA-sequencing data from this study have been submitted to the Gene Expression Omnibus (GEO) database under the accession number GSE154927 and GSE154930 for the bulk and single-cell RNAseq data, respectively.

The following data sets were generated
The following previously published data sets were used

Article and author information

Author details

  1. Andrea Sacchetti

    Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  2. Miriam Teeuwssen

    Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  3. Mathijs Verhagen

    Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0003-3126-8379
  4. Rosalie Joosten

    Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  5. Tong Xu

    Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Roberto Stabile

    Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  7. Berdine van der Steen

    Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  8. Martin M Watson

    Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  9. Alem Gusinac

    Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  10. Won Kyu Kim

    Natural Product Research Center, Korea Institute of Science and Technology, Gangneung, Republic of Korea
    Competing interests
    The authors declare that no competing interests exist.
  11. Inge Ubink

    Department of Surgical Oncology, Cancer Centre, University Medical Centre Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  12. Harmen JG Van de Werken

    Department of Cell Biology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-9794-1477
  13. Arianna Fumagalli

    n/a, Princess Máxima Center for Pediatric Oncology, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  14. Madelon Paauwe

    n/a, Cancer Research UK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
  15. Jacco Van Rheenen

    Van Rheenen group, Netherlands Cancer Institute, Amterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  16. Owen J Sansom

    Institute of Cancer Sciences, CRUK Beatson Institute, Glasgow, United Kingdom
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9540-3010
  17. Onno Kranenburg

    Department of Surgical Oncology, Cancer Centre, University Medical Centre Utrecht, Utrecht, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  18. Riccardo Fodde

    Pathology, Erasmus MC, Rotterdam, Netherlands
    For correspondence
    r.fodde@erasmusmc.nl
    Competing interests
    The authors declare that no competing interests exist.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-9839-4324

Funding

Maag Lever Darm Stichting (FP 15-09)

  • Riccardo Fodde

KWF Kankerbestrijding (EMCR 2015-8090)

  • Riccardo Fodde

Cancer Research UK (A17196/A21139)

  • Owen J Sansom

The funders had no role in study design, data collection and interpretation, or the decision to submit the work for publication.

Ethics

Animal experimentation: All protocols involving animals were approved by the Dutch Animal Experimental Committee and were conformed to the Code of Practice for Animal Experiments in Cancer Research established by the Netherlands Inspectorate for Health Protections, Commodities and Veterinary Public health (The Hague, the Netherlands, 1999).

Copyright

© 2021, Sacchetti et al.

This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.

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  1. Andrea Sacchetti
  2. Miriam Teeuwssen
  3. Mathijs Verhagen
  4. Rosalie Joosten
  5. Tong Xu
  6. Roberto Stabile
  7. Berdine van der Steen
  8. Martin M Watson
  9. Alem Gusinac
  10. Won Kyu Kim
  11. Inge Ubink
  12. Harmen JG Van de Werken
  13. Arianna Fumagalli
  14. Madelon Paauwe
  15. Jacco Van Rheenen
  16. Owen J Sansom
  17. Onno Kranenburg
  18. Riccardo Fodde
(2021)
Phenotypic plasticity underlies local invasion and distant metastasis in colon cancer
eLife 10:e61461.
https://doi.org/10.7554/eLife.61461

Share this article

https://doi.org/10.7554/eLife.61461

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