Reversing chemorefraction in colorectal cancer cells by controlling mucin secretion
Cantero-Recasens, Gerard (Hospital Universitari Vall d'Hebron)
Alonso-Marañón, Josune (Institut Hospital del Mar d'Investigacions Mèdiques)
Lobo-Jarne, Teresa (Institut Hospital del Mar d'Investigacions Mèdiques)
Garrido, Marta (Institut Hospital del Mar d'Investigacions Mèdiques)
Iglesias, Mar (Institut Hospital del Mar d'Investigacions Mèdiques)
Espinosa, Lluis (Institut Hospital del Mar d'Investigacions Mèdiques)
Malhotra, Vivek (Institució Catalana de Recerca i Estudis Avançats)
Universitat Autònoma de Barcelona

Date:	2022
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.
Grants:	Ministerio de Economía y Competitividad BFU2013-44188-P Instituto de Salud Carlos III PI19-00013
Rights:	Aquest document està subjecte a una llicència d'ús Creative Commons. Es permet la reproducció total o parcial, la distribució, la comunicació pública de l'obra i la creació d'obres derivades, fins i tot amb finalitats comercials, sempre i quan es reconegui l'autoria de l'obra original.
Language:	Anglès
Document:	Article ; recerca ; Versió publicada
Subject:	Chemotherapy ; Colorectal cancer ; Mucins ; KChIP3 ; Chemoresistance ; 5-FU+iri ; Human
Published in:	eLife, Vol. 11 (february 2022) , ISSN 2050-084X

DOI: 10.7554/eLife.73926
PMID: 35131032

17 p, 9.0 MB

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