Liver X receptor unlinks intestinal regeneration and tumorigenesis

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dc.contributor.authorDas, Srustidhar
dc.contributor.authorParigi S., Martina
dc.contributor.authorLuo, Xinxin
dc.contributor.authorFransson, Jennifer
dc.contributor.authorKern, Bianca C.
dc.contributor.authorOkhovat, Ali
dc.contributor.authorDiaz, Oscar E.
dc.contributor.authorSorini, Chiara
dc.contributor.authorCzarnewski, Paulo
dc.contributor.authorWebb, Anna T.
dc.contributor.authorMorales, Rodrigo A
dc.contributor.authorLebon, Sacha
dc.contributor.authorMonasterio, Gustavo
dc.contributor.authorCastillo, Francisca
dc.contributor.authorTripathi, Kumar P.
dc.contributor.authorHe, Ning
dc.contributor.authorPelczar, Penelope
dc.contributor.authorSchaltenberg, Nicola
dc.contributor.authorDe la Fuente, Marjorie
dc.contributor.authorLópez-Köstner, Francisco
dc.contributor.authorNylén, Susanne
dc.contributor.authorLarsen, Hjalte List
dc.contributor.authorKuiper, Raoul
dc.contributor.authorAntonson, Per
dc.contributor.authorHermoso, Marcela A
dc.contributor.authorHuber, Samuel
dc.contributor.authorBiton, Moshe
dc.contributor.authorScharaw, Sandra
dc.contributor.authorGustafsson, Jan-Åke
dc.contributor.authorKatajisto, Pekka
dc.contributor.authorVillablanca, Eduardo J.
dc.date.accessioned2025-01-16T18:26:51Z
dc.date.available2025-01-16T18:26:51Z
dc.date.issued2024-10-17
dc.description.abstractUncontrolled regeneration leads to neoplastic transformation1-3. The intestinal epithelium requires precise regulation during continuous homeostatic and damage-induced tissue renewal to prevent neoplastic transformation, suggesting that pathways unlinking tumour growth from regenerative processes must exist. Here, by mining RNA-sequencing datasets from two intestinal damage models4,5 and using pharmacological, transcriptomics and genetic tools, we identified liver X receptor (LXR) pathway activation as a tissue adaptation to damage that reciprocally regulates intestinal regeneration and tumorigenesis. Using single-cell RNA sequencing, intestinal organoids, and gain- and loss-of-function experiments, we demonstrate that LXR activation in intestinal epithelial cells induces amphiregulin (Areg), enhancing regenerative responses. This response is coordinated by the LXR-ligand-producing enzyme CYP27A1, which was upregulated in damaged intestinal crypt niches. Deletion of Cyp27a1 impaired intestinal regeneration, which was rescued by exogenous LXR agonists. Notably, in tumour models, Cyp27a1 deficiency led to increased tumour growth, whereas LXR activation elicited anti-tumour responses dependent on adaptive immunity. Consistently, human colorectal cancer specimens exhibited reduced levels of CYP27A1, LXR target genes, and B and CD8 T cell gene signatures. We therefore identify an epithelial adaptation mechanism to damage, whereby LXR functions as a rheostat, promoting tissue repair while limiting tumorigenesis.
dc.identifier.citationNature, (2024) p. 1-44.
dc.identifier.doihttps://doi.org/10.1038/s41586-024-08247-6
dc.identifier.issn0028-0836
dc.identifier.issne1476-4687
dc.identifier.orcidhttps://orcid.org/0000-0003-0577-7604
dc.identifier.urihttp://hdl.handle.net/20.500.12254/4037
dc.language.isoen
dc.publisherSpringer Nature
dc.rightsAtribución-NoComercial-CompartirIgual 3.0 Chile (CC BY-NC-SA 3.0 CL)
dc.rights.urihttp://creativecommons.org/licenses/by-nc-sa/3.0/cl/
dc.subjectIntestinal regeneration
dc.subjectColon cancer
dc.subjectIntestinal stem cells
dc.subjectStem-cell research
dc.titleLiver X receptor unlinks intestinal regeneration and tumorigenesis
dc.typeArticle
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