Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
- Vall d'Hebron Institut de Recerca, Spain
- Institut Mar d'Investigacions Mèdiques, Spain
- 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
Article and author information
Author details
Gerard Cantero-Recasens
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
- Kelly G Ten Hagen, National Institutes of Health, United States
Version history
- Received: September 17, 2021
- Preprint posted: September 19, 2021 (view preprint)
- Accepted: February 4, 2022
- Accepted Manuscript published: February 8, 2022 (version 1)
- 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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Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
eLife 11:e73926.
https://doi.org/10.7554/eLife.73926
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