Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
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- dc.contributor.author Cantero Recasens, Gerard, 1984-
- dc.contributor.author Alonso-Marañón, Josune
- dc.contributor.author Lobo-Jarne, Teresa
- dc.contributor.author Garrido, Marta
- dc.contributor.author Iglesias Coma, Mar
- dc.contributor.author Espinosa Blay, Lluís
- dc.contributor.author Malhotra, Vivek
- dc.date.accessioned 2022-03-31T07:12:46Z
- dc.date.available 2022-03-31T07:12:46Z
- dc.date.issued 2022
- dc.description.abstract Fifteen percent of colorectal cancer (CRC) cells exhibit a mucin hypersecretory phenotype, which is suggested to provide resistance to immune surveillance and chemotherapy. We now formally show that CRC 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 a 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 + irinotecan (5-FU+iri.) compared to control cells, whereas KChIP3-overexpressing cells are 10 times more sensitive to killing by chemotherapeutics. A 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 CRC cells and other mucinous tumours.
- dc.description.sponsorship This work was funded by grants from the Spanish Ministry of Economy and Competitiveness (BFU2013-44188-P to VM) and FEDER Funds, and Instituto de Salud Carlos III (PI19-00013 to LE). We acknowledge support of the Spanish Ministry of Economy and Competitiveness, through the Programmes 'Centro de Excelencia Severo Ochoa 2013–2017' (SEV-2012-0208 and SEV-2013-0347) and Maria de Maeztu Units of Excellence in R&D (MDM-2015-0502). This work reflects only the authors’ views, and the EU Community is not liable for any use that may be made of the information contained therein.
- dc.format.mimetype application/pdf
- dc.identifier.citation Cantero-Recasens G, Alonso-Marañón J, Lobo-Jarne T, Garrido M, Iglesias M, Espinosa L, Malhotra V. Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion. Elife. 2022 Feb 8;11:e73926. DOI: 10.7554/eLife.73926
- dc.identifier.doi http://dx.doi.org/10.7554/eLife.73926
- dc.identifier.issn 2050-084X
- dc.identifier.uri http://hdl.handle.net/10230/52803
- dc.language.iso eng
- dc.publisher eLife
- dc.relation.ispartof Elife. 2022 Feb 8;11:e73926
- dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2013-44188-P
- dc.rights © 2022, Cantero-Recasens et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
- dc.rights.accessRights info:eu-repo/semantics/openAccess
- dc.rights.uri http://creativecommons.org/licenses/by/4.0/
- dc.subject.keyword 5-FU+iri.
- dc.subject.keyword KChIP3
- dc.subject.keyword Cell biology
- dc.subject.keyword Chemoresistance
- dc.subject.keyword Chemotherapy
- dc.subject.keyword Colorectal cancer
- dc.subject.keyword Human
- dc.subject.keyword Mucins
- dc.title Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
- dc.type info:eu-repo/semantics/article
- dc.type.version info:eu-repo/semantics/publishedVersion