Alternative splicing downstream of EMT enhances phenotypic plasticity and malignant behaviour in colon cancer

  1. Tong Xu
  2. Mathijs Verhagen
  3. Rosalie Joosten
  4. Wenjie Sun
  5. Andrea Sacchetti
  6. Leonel Munoz Sagredo
  7. Véronique Orian-Rousseau
  8. Riccardo Fodde  Is a corresponding author
  1. Erasmus MC, Netherlands
  2. Institute Curie, France
  3. Karlsruhe Institute of Technology, Germany

Abstract

Phenotypic plasticity allows carcinoma cells to transiently acquire the quasi-mesenchymal features necessary to detach from the primary mass and proceed along the invasion-metastasis cascade. A broad spectrum of epigenetic mechanisms is likely to cause the epithelial-to-mesenchymal (EMT) and mesenchymal-to-epithelial (MET) transitions necessary to allow local dissemination and distant metastasis. Here, we report on the role played by alternative splicing (AS) in eliciting phenotypic plasticity in epithelial malignancies with focus on colon cancer. By taking advantage of the coexistence of subpopulations of fully epithelial (EpCAMhi) and quasi-mesenchymal and highly metastatic (EpCAMlo) cells in conventional human cancer cell lines, we here show that the differential expression of ESRP1 and other RNA-binding proteins (RBPs) downstream of the EMT master regulator ZEB1, alters the AS pattern of a broad spectrum of targets including CD44 and NUMB, thus resulting in the generation of specific isoforms functionally associated with increased invasion and metastasis. Additional functional and clinical validation studies indicate that both the newly identified RBPs and the CD44s and NUMB2/4 splicing isoforms promote local invasion and distant metastasis and are associated with poor survival in colon cancer. The systematic elucidation of the spectrum of EMT-related RBPs and AS targets in epithelial cancers, apart from the insights in the mechanisms underlying phenotypic plasticity, will lead to the identification of novel and tumor-specific therapeutic targets.

Data availability

The RNA-sequencing data from this study have been submitted to the Gene Expression Omnibus (GEO) database under the accession number GSE192877. Other data referenced in this study are publicly available and can be accessed from the GEO using GSE154927, GSE154730 and Synapse using identifier syn2623706 .

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

Article and author information

Author details

  1. Tong Xu

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

    Department of 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
  3. Rosalie Joosten

    Department of Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  4. Wenjie Sun

    Laboratory of Genetics and Developmental Biology, Institute Curie, Paris, France
    Competing interests
    The authors declare that no competing interests exist.
  5. Andrea Sacchetti

    Department of Pathology, Erasmus MC, Rotterdam, Netherlands
    Competing interests
    The authors declare that no competing interests exist.
  6. Leonel Munoz Sagredo

    Institute of Biological and Chemical Systems - Functional Molecular Systems (IBCS FMS), Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  7. Véronique Orian-Rousseau

    Institute of Biological and Chemical Systems - Functional Molecular Systems (IBCS FMS), Karlsruhe Institute of Technology, Karlsruhe, Germany
    Competing interests
    The authors declare that no competing interests exist.
  8. Riccardo Fodde

    Department of 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

China Scholarship Council (201806300047)

  • Tong Xu

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

Reviewing Editor

  1. Lynne-Marie Postovit, University of Alberta, Canada

Ethics

Animal experimentation: All mice experiments were implemented according to the Code of Practice for Animal Experiment in Cancer Research from the Netherlands Inspectorate for Health Protections, Commodities and Veterinary Public Health. Permit number AVD1010020171344.

Version history

  1. Preprint posted: March 1, 2022 (view preprint)
  2. Received: July 19, 2022
  3. Accepted: November 7, 2022
  4. Accepted Manuscript published: November 8, 2022 (version 1)
  5. Version of Record published: November 18, 2022 (version 2)

Copyright

© 2022, Xu 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. Tong Xu
  2. Mathijs Verhagen
  3. Rosalie Joosten
  4. Wenjie Sun
  5. Andrea Sacchetti
  6. Leonel Munoz Sagredo
  7. Véronique Orian-Rousseau
  8. Riccardo Fodde
(2022)
Alternative splicing downstream of EMT enhances phenotypic plasticity and malignant behaviour in colon cancer
eLife 11:e82006.
https://doi.org/10.7554/eLife.82006

Share this article

https://doi.org/10.7554/eLife.82006

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