2. Academic Validation
  3. Liver X receptor unlinks intestinal regeneration and tumorigenesis

Liver X receptor unlinks intestinal regeneration and tumorigenesis

  • Nature. 2024 Nov 20. doi: 10.1038/s41586-024-08247-6.
Srustidhar Das # 1 2,  S Martina Parigi # 3 4 5,  Xinxin Luo # 3 4,  Jennifer Fransson 3 4,  Bianca C Kern 3 4,  Ali Okhovat 3 4 6,  Oscar E Diaz 3 4,  Chiara Sorini 3 4,  Paulo Czarnewski 3 4 7,  Anna T Webb 8,  Rodrigo A Morales 3 4,  Sacha Lebon 9,  Gustavo Monasterio 3 4,  Francisca Castillo 3 4,  Kumar P Tripathi 3 4,  Ning He 3 4,  Penelope Pelczar 10,  Nicola Schaltenberg 10,  Marjorie De la Fuente 11 12,  Francisco López-Köstner 13,  Susanne Nylén 14,  Hjalte List Larsen 15,  Raoul Kuiper 16 17,  Per Antonson 18,  Marcela A Hermoso 12,  Samuel Huber 10,  Moshe Biton 9,  Sandra Scharaw 8 19,  Jan-Åke Gustafsson 18 20,  Pekka Katajisto 8 21,  Eduardo J Villablanca 22 23 24
Affiliations

Affiliations

  • 1 Division of Immunology and Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden. srustidhar.das@ki.se.
  • 2 Center of Molecular Medicine, Stockholm, Sweden. srustidhar.das@ki.se.
  • 3 Division of Immunology and Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden.
  • 4 Center of Molecular Medicine, Stockholm, Sweden.
  • 5 Robin Chemers Neustein Laboratory of Mammalian Cell Biology and Development, The Rockefeller University, New York, NY, USA.
  • 6 Structural Genomics Consortium, Division of Rheumatology, Department of Medicine Solna, Karolinska Institute and University Hospital, Stockholm, Sweden.
  • 7 Science for Life Laboratory, Department of Biochemistry and Biophysics, National Bioinformatics Infrastructure Sweden, Stockholm University, Solna, Sweden.
  • 8 Department of Cell and Molecular Biology, Karolinska Institutet, Solna, Sweden.
  • 9 Department of Immunology and Regenerative Biology, Weizmann Institute of Science, Rehovot, Israel.
  • 10 I. Medizinische Klinik, Universitätsklinikum Hamburg-Eppendorf, Hamburg, Germany.
  • 11 Center of Biomedical Research (CIBMED), School of Medicine, Faculty of Medicine-Clinica Las Condes, Universidad Finis Terrae, Santiago, Chile.
  • 12 Laboratory of Innate Immunity, Program of Immunology, Institute of Biomedical Sciences, Faculty of Medicine, Universidad de Chile, Santiago, Chile.
  • 13 Centro de Enfermedades Digestivas, Programa Enfermedad Inflamatoria Intestinal, Clínica Universidad de Los Andes, Universidad de Los Andes, Santiago, Chile.
  • 14 Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden.
  • 15 Novo Nordisk Foundation Center for Stem Cell Medicine (reNEW), University of Copenhagen, Copenhagen, Denmark.
  • 16 Section for Aquatic Biosecurity Research, Norwegian Veterinary Institute, Ås, Norway.
  • 17 Department of Laboratory Medicine, Karolinska Institutet, Huddinge, Sweden.
  • 18 Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
  • 19 Max Planck Institute of Molecular Cell Biology and Genetics, Dresden, Germany.
  • 20 Center for Nuclear Receptors and Cell Signaling, Department of Biology and Biochemistry, University of Houston, Houston, TX, USA.
  • 21 Institute of Biotechnology, University of Helsinki, Helsinki, Finland.
  • 22 Division of Immunology and Respiratory Medicine, Department of Medicine Solna, Karolinska Institutet and University Hospital, Stockholm, Sweden. eduardo.villablanca@ki.se.
  • 23 Center of Molecular Medicine, Stockholm, Sweden. eduardo.villablanca@ki.se.
  • 24 Clinical Immunology and Transfusion Medicine, Karolinska University Hospital, Stockholm, Sweden. eduardo.villablanca@ki.se.
  • # Contributed equally.
PMID: 39567700 DOI: 10.1038/s41586-024-08247-6
Abstract

Uncontrolled 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.

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