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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.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.issn 2050-084X
dc.identifier.uri http://hdl.handle.net/10230/52803
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.language.iso eng
dc.publisher eLife
dc.relation.ispartof Elife. 2022 Feb 8;11:e73926
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.uri http://creativecommons.org/licenses/by/4.0/
dc.title Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
dc.type info:eu-repo/semantics/article
dc.identifier.doi http://dx.doi.org/10.7554/eLife.73926
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.relation.projectID info:eu-repo/grantAgreement/ES/1PE/BFU2013-44188-P
dc.rights.accessRights info:eu-repo/semantics/openAccess
dc.type.version info:eu-repo/semantics/publishedVersion


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