Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion

  1. Gerard Cantero-Recasens  Is a corresponding author
  2. Josune Alonso-Marañón
  3. Teresa Lobo-Jarne
  4. Marta Garrido
  5. Mar Iglesias
  6. Lluis Espinosa  Is a corresponding author
  7. Vivek Malhotra  Is a corresponding author
  1. Vall d'Hebron Institut de Recerca, Spain
  2. Institut Mar d'Investigacions Mèdiques, Spain
  3. The Barcelona Institute of Science and Technology, Spain

Abstract

15% of colorectal cancers (CRC) cells exhibit a mucin hypersecretory phenotype, which is suggested to provide resistance to immune surveillance and chemotherapy. We now formally show that colorectal cancer cells build a barrier to chemotherapeutics by increasing mucins' secretion. We show that low levels of KChIP3, a negative regulator of mucin secretion (Cantero-Recasens et al., 2018), is a risk factor for CRC patients' relapse in subset of untreated tumours. Our results also reveal that cells depleted of KChIP3 are four times more resistant (measured as cell viability and DNA damage) to chemotherapeutics 5-Fluorouracil plus Irinotecan (5-FU+iri.) compared to control cells, whereas KChIP3 overexpressing cells are 10 times more sensitive to killing by chemotherapeutics. Similar increase in tumour cell death is observed upon chemical inhibition of mucin secretion by the sodium/calcium exchanger (NCX) blockers (Mitrovic et al., 2013). Finally, sensitivity of CRC patient-derived organoids to 5-FU+iri increases 40-fold upon mucin secretion inhibition. Reducing mucin secretion thus provides a means to control chemoresistance of mucinous colorectal cancer cells and other mucinous tumours.

Data availability

All data generated or analysed are included in the manuscript

The following previously published data sets were used

Article and author information

Author details

  1. Gerard Cantero-Recasens

    Renal Physiopathology Group, Vall d'Hebron Institut de Recerca, Barcelona, Spain
    For correspondence
    gerard.cantero@vhir.org
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6452-782X
  2. Josune Alonso-Marañón

    Cancer Research Program, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    Competing interests
    No competing interests declared.
  3. Teresa Lobo-Jarne

    Cancer Research Program, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    Competing interests
    No competing interests declared.
  4. Marta Garrido

    Cancer Research Program, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    Competing interests
    No competing interests declared.
  5. Mar Iglesias

    Department of Pathology, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    Competing interests
    No competing interests declared.
  6. Lluis Espinosa

    Cancer Research Program, Institut Mar d'Investigacions Mèdiques, Barcelona, Spain
    For correspondence
    lespinosa@imim.es
    Competing interests
    No competing interests declared.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0002-2897-4099
  7. Vivek Malhotra

    Centre for Genomic Regulation, The Barcelona Institute of Science and Technology, Barcelona, Spain
    For correspondence
    vivek.malhotra@crg.eu
    Competing interests
    Vivek Malhotra, Senior editor, eLife.
    ORCID icon "This ORCID iD identifies the author of this article:" 0000-0001-6198-7943

Funding

Ministerio de Economía, Industria y Competitividad, Gobierno de España (BFU2013-44188-P)

  • Vivek Malhotra

Instituto de Salud Carlos III (PI19-00013)

  • Lluis Espinosa

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

Reviewing Editor

  1. Kelly G Ten Hagen, National Institutes of Health, United States

Version history

  1. Received: September 17, 2021
  2. Preprint posted: September 19, 2021 (view preprint)
  3. Accepted: February 4, 2022
  4. Accepted Manuscript published: February 8, 2022 (version 1)
  5. Version of Record published: February 15, 2022 (version 2)

Copyright

© 2022, Cantero-Recasens 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. Gerard Cantero-Recasens
  2. Josune Alonso-Marañón
  3. Teresa Lobo-Jarne
  4. Marta Garrido
  5. Mar Iglesias
  6. Lluis Espinosa
  7. Vivek Malhotra
(2022)
Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
eLife 11:e73926.
https://doi.org/10.7554/eLife.73926

Share this article

https://doi.org/10.7554/eLife.73926

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