Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion

Cantero Recasens, Gerard, 1984-; Alonso-Marañón, Josune; Lobo-Jarne, Teresa; Garrido, Marta; Iglesias Coma, Mar; Espinosa Blay, Lluís; Malhotra, Vivek

doi:http://dx.doi.org/10.7554/eLife.73926

Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion

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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

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.