Vitamin D differentially regulates colon stem cells in patient-derived normal and tumor organoids

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• dc.contributor.author Fernández Barral, Asunción
• dc.contributor.author Costales-Carrera, Alba
• dc.contributor.author Buira, Sandra P.
• dc.contributor.author Jung, Peter
• dc.contributor.author Ferrer Mayorga, Gemma
• dc.contributor.author Larriba, María Jesús
• dc.contributor.author Bustamante Madrid, Pilar
• dc.contributor.author Domínguez, Orlando
• dc.contributor.author Real, Francisco X.
• dc.contributor.author Guerra Pastrián, Laura
• dc.contributor.author Lafarga, Miguel
• dc.contributor.author García-Olmo, Damián
• dc.contributor.author Cantero, Ramón
• dc.contributor.author Del Peso, Luis
• dc.contributor.author Batlle Gómez, Eduard
• dc.contributor.author Rojo, Federico
• dc.contributor.author Muñoz, Alberto
• dc.contributor.author Barbáchano, Antonio
• dc.date.accessioned 2019-10-03T10:37:16Z
• dc.date.available 2019-10-03T10:37:16Z
• dc.date.issued 2019
• dc.description.abstract Intestine is a major target of vitamin D and several studies indicate an association between vitamin D deficiency and inflammatory bowel diseases (IBD), but also increased colorectal cancer (CRC) risk and mortality. However, the putative effects of 1α,25-dihydroxyvitamin D3 (calcitriol), the active vitamin D metabolite, on human colonic stem cells are unknown. Here we show by immunohistochemistry and RNAscope in situ hybridization that vitamin D receptor (VDR) is unexpectedly expressed in LGR5+ colon stem cells in human tissue and in normal and tumor organoid cultures generated from patient biopsies. Interestingly, normal and tumor organoids respond differentially to calcitriol with profound and contrasting changes in their transcriptomic profiles. In normal organoids, calcitriol upregulates stemness-related genes, such as LGR5, SMOC2, LRIG1, MSI1, PTK7, and MEX3A, and inhibits cell proliferation. In contrast, in tumor organoids calcitriol has little effect on stemness-related genes while it induces a differentiated phenotype, and variably reduces cell proliferation. Concordantly, electron microscopy showed that calcitriol does not affect the blastic undifferentiated cell phenotype in normal organoids but it induces a series of differentiated features in tumor organoids. Our results constitute the first demonstration of a regulatory role of vitamin D on human colon stem cells, indicating a homeostatic effect on colon epithelium with relevant implications in IBD and CRC.
• dc.description.sponsorship The studies were funded by Networks of Excellence from Spanish Ministry of Science, Innovation and Universities (MICINN) SAF2016‐76377‐R, ‘Nuclear Receptors in Cancer, Metabolism and Inflammation’ (NuRCaMeIn) SAF2017‐90604‐REDT to A.M., ISCIII‐Biomedical Research Networking Centres‐Oncology (CIBERONC) CB16/12/00273 to A.M. and A.B.; CB16/12/00453 to F.X.R.; CB16/12/00342 to E.B. and CB16/12/00241 to F.R. ISCIII‐Biomedical Research Networking Centres‐Respiratory Diseases (CIBERES) CB15/00037 to L.dP, and ISCIII‐FEDER PI15/00934 to F.R.
• dc.format.mimetype application/pdf
• dc.identifier.citation Fernández-Barral A, Costales-Carrera A, Buira SP, Jung P, Ferrer-Mayorga G, Larriba MJ et al. Vitamin D differentially regulates colon stem cells in patient-derived normal and tumor organoids. FEBS J. 2020;287(1):53-72. DOI: 10.1111/febs.14998
• dc.identifier.doi http://dx.doi.org/10.1111/febs.14998
• dc.identifier.issn 1742-464X
• dc.identifier.uri http://hdl.handle.net/10230/42377
• dc.language.iso eng
• dc.publisher Wiley-Blackwell
• dc.relation.ispartof FEBS J. 2020;287(1):53-72
• dc.relation.projectID info:eu-repo/grantAgreement/ES/1PE/SAF2016‐76377‐R
• dc.relation.projectID info:eu-repo/grantAgreement/ES/2PE/SAF2017‐90604‐REDT
• dc.rights © 2019 The Authors. The FEBS Journal published by John Wiley & Sons Ltd on behalf of Federation of European Biochemical Societies. This is an open access article under the terms of the Creative Commons Attribution‐NonCommercial‐NoDerivs License, which permits use and distribution in any medium, provided the original work is properly cited, the use is non‐commercial and no modifications or adaptations are made.
• dc.rights.accessRights info:eu-repo/semantics/openAccess
• dc.rights.uri http://creativecommons.org/licenses/by-nc-nd/4.0/
• dc.subject.keyword Colon cancer
• dc.subject.keyword Colon stem cells
• dc.subject.keyword Organoids
• dc.subject.keyword Stemness genes
• dc.subject.keyword Vitamin D
• dc.title Vitamin D differentially regulates colon stem cells in patient-derived normal and tumor organoids
• dc.type info:eu-repo/semantics/article
• dc.type.version info:eu-repo/semantics/publishedVersion