Liver X receptor unlinks intestinal regeneration and tumorigenesis

Uncontrolled regeneration leads to neoplastic transformation<sup>1-3</sup>. 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 models<sup>4,5</sup> 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.

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Journal
Nature
Published
2024-11-20
DOI
https://doi.org/10.1038/s41586-024-08247-6
Citations
25
Primary Topic
Phagocytosis and Immune Regulation
Type
article
Field-Weighted Citation Impact
6.01
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article

Liver X receptor unlinks intestinal regeneration and tumorigenesis

Xinxin Luo, Raoul Kuiper, Bianca C. Kern, Marjorie De la Fuente et al.
25 citations
Nature
Phagocytosis and Immune Regulation
6.01
article

Liver X receptor unlinks intestinal regeneration and tumorigenesis

Xinxin Luo, Raoul Kuiper, Bianca C. Kern, Marjorie De la Fuente, Pekka Katajisto, Sacha Lebon, Jennifer Fransson, Rodrigo A. Morales, Penelope Pelczar, Per Antonson, Hjalte List Larsen, Oscar E. Diaz, Chiara Sorini, Kumar Parijat Tripathi, Gustavo Monasterio, Moshe Biton, Paulo Czarnewski, Francisca Castillo, Srustidhar Das, Francisco López-Köstner, Nicola Schaltenberg, Sara Martina Parigi, Marcela A. Hermoso, Susanne Nylén, Sandra Scharaw, Anna Webb, Eduardo J. Villablanca, Samuel Huber, He Ning, Jan-Åke Gustafsson, Ali Okhovat
article en
25 citations

Abstract

Uncontrolled regeneration leads to neoplastic transformation<sup>1-3</sup>. 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 models<sup>4,5</sup> 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.

NatureVol. 637(8048)
Swedish Defence University (SE), University of Copenhagen (DK), Karolinska University Hospital (SE), University of Helsinki (FI), Universität Hamburg (DE), Stockholm University (SE), Universidad de Los Andes, Chile (CL), Science for Life Laboratory (SE), Novo Nordisk Foundation (DK), Structural Genomics Consortium (CA), Karolinska Institutet (SE), Clínica Las Condes (CL), ESI Group (Sweden) (SE), University Medical Center Hamburg-Eppendorf (DE), Finis Terrae University (CL), Max Planck Institute of Molecular Cell Biology and Genetics (DE), Norwegian Veterinary Institute (NO), University of Houston (US), Weizmann Institute of Science (IL), University of Chile (CL), Rockefeller University (US)
Good health and well-being
Openalex Percentile: Top 3%
Phagocytosis and Immune Regulation
6.01
DOIOpen Access PDFOpenAlex
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