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.
| Originalsprog | Engelsk |
|---|---|
| Tidsskrift | Nature |
| Vol/bind | 637 |
| Sider (fra-til) | 1198–1206 |
| Antal sider | 44 |
| ISSN | 0028-0836 |
| DOI | |
| Status | Udgivet - 2024 |
Bibliografisk note
Funding Information:We thank the Villablanca laboratory members for discussions; N. Nedelsky for editorial assistance; S. Inampudi and M. Shaik for their help with experiments; the staff at the FENO facility for tissue processing. The computations/data handling was enabled by resources provided by the Swedish National Infrastructure for Computing (SNIC), under project number SNIC 2017/7-445 and partially funded by the Swedish Research Council through grant agreement no. 2018-05973. We also thank the staff at the National Bioinformatics Infrastructure Sweden (NBIS) long-term support. The analysis pipeline for salivary glands has been made possible in part by BioImage Informatics Facility, a unit of the National Bioinformatics Infrastructure Sweden NBIS, with funding from SciLifeLab, National Microscopy Infrastructure NMI (VR-RFI 2019-00217) and Chan Zuckerberg Initiative DAF (DAF2021-225261, https://doi.org/10.37921/644085ggkbos , an advised fund of Silicon Valley Community Foundation, https://doi.org/10.13039/100014989 ). The Novo Nordisk Foundation Centre for Stem Cell Medicine (reNEW) are supported by a Novo Nordisk Foundation grant number NNF21CC0073729. This project has received funding from the Innovative Medicines Initiative 2 Joint Undertaking (JU) under grant agreement No 875510. The JU receives support from the European Union\u2019s Horizon 2020 research and innovation programme and EFPIA and Ontario Institute for Cancer Research, Royal Institution for the Advancement of Learning McGill University, Kungliga Tekniska Hoegskolan, Diamond Light Source Limited. This communication reflects the views of the authors and the JU is not liable for any use that may be made of the information contained herein. X.L. was supported by grants from China Scholarship Council (nr. 201907930012). S.D. was supported by Cancerfonden (CAN 2016/1206), \u00C5ke Weibergs Stiftelse (M21-0074, M22-0048, M23-0179); and E.J.V. by grants from the Swedish Research Council VR (K2015-68X-22765-01-6, 2018-02533 and 2021-01277), FORMAS (FR-2016/0005 and 2022-01066), Cancerfonden (19 0395 Pj and 22 2060 Pj), European Research Council (ERC) Synergy Grant 101118531, and Wallenberg Academy Fellow (WAF) program (2019.0315 and 2024.0135).
Publisher Copyright:
© The Author(s) 2024.