Cantero Recasens, Gerard, 1984-Alonso-Marañón, JosuneLobo-Jarne, TeresaGarrido, MartaIglesias Coma, MarEspinosa Blay, LluísMalhotra, Vivek2022-03-312022-03-312022Cantero-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.739262050-084Xhttp://hdl.handle.net/10230/52803Fifteen 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.application/pdfeng© 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.info:eu-repo/semantics/articlehttp://dx.doi.org/10.7554/eLife.739265-FU+iri.KChIP3Cell biologyChemoresistanceChemotherapyColorectal cancerHumanMucinsinfo:eu-repo/semantics/openAccess