Gut dysbiosis conveys psychological stress to activate LRP5/β-catenin pathway promoting cancer stemness
Psychological stress causes gut microbial dysbiosis and cancer progression, yet how gut microbiota determines psychological stress-induced tumor development remains unclear. Here we showed that psychological stress promotes breast tumor growth and cancer stemness, an outcome that depends on gut microbiota in germ-free and antibiotic-treated mice. Metagenomic and metabolomic analyses revealed that psychological stress markedly alters the composition and abundance of gut microbiota, especially Akkermansia muciniphila (A. muciniphila), and decreases short-chain fatty acid butyrate. Supplement of active A. muciniphila, butyrate or a butyrate-producing high fiber diet dramatically reversed the oncogenic property and anxiety-like behavior of psychological stress in a murine spontaneous tumor model or an orthotopic tumor model. Mechanistically, RNA sequencing analysis screened out that butyrate decreases LRP5 expression to block the activation of Wnt/β-catenin signaling pathway, dampening breast cancer stemness. Moreover, butyrate as a HDAC inhibitor elevated histone H3K9 acetylation level to transcriptionally activate ZFP36, which further accelerates LRP5 mRNA decay by binding adenine uridine-rich (AU-rich) elements of LRP5 transcript. Clinically, fecal A. muciniphila and serum butyrate were inversely correlated with tumoral LRP5/β-catenin expression, poor prognosis and negative mood in breast cancer patients. Altogether, our findings uncover a microbiota-dependent mechanism of psychological stress-triggered cancer stemness, and provide both clinical biomarkers and potential therapeutic avenues for cancer patients undergoing psychological stress.
Authors
- Keith W. Kelley (ORCID: https://orcid.org/0000-0002-6837-8793)
- Xiaoli Nie (ORCID: https://orcid.org/0000-0003-4296-1953)
- Yingrui Zhao
- Cenxin Wang
- Guowang Xu (ORCID: https://orcid.org/0000-0003-4298-3554)
- Dekang Lv
- Qiulong Yan
- Anqi Cai
- Huandong Luo
- Keyu Su (ORCID: https://orcid.org/0000-0003-2198-1234)
- Xianxian Liu
- Xu Wang (ORCID: https://orcid.org/0000-0001-6920-0375)
- Bin He (ORCID: https://orcid.org/0000-0001-7621-1910)
- Cui Bai (ORCID: https://orcid.org/0000-0001-5273-1081)
- Zhi Lv (ORCID: https://orcid.org/0009-0009-6072-8160)
- Jinxin Lü (ORCID: https://orcid.org/0000-0002-0929-0804)
- Quentin Liu (ORCID: https://orcid.org/0000-0002-0999-9805)
- Fei Peng (ORCID: https://orcid.org/0000-0003-0316-2251)
- Xiaoyu Zhang (ORCID: https://orcid.org/0000-0003-0968-5969)
- Zhao Zhang (ORCID: https://orcid.org/0000-0001-9345-3663)
- Xinyi Chen (ORCID: https://orcid.org/0000-0002-0638-1380)
- Congcong Liu (ORCID: https://orcid.org/0000-0001-5920-9114)
- Ziyu Zhang (ORCID: https://orcid.org/0000-0002-1982-112X)
- Lingzhi Xu (ORCID: https://orcid.org/0000-0001-7150-4757)
- Sijia Zheng (ORCID: https://orcid.org/0000-0002-1700-4927)
- Zhihang Liu (ORCID: https://orcid.org/0009-0000-6281-418X)
- Xinyu Liu (ORCID: https://orcid.org/0009-0005-7279-5476)
- Yunkun Zhang
- Fan An
- Yuanyuan Jiang
- Yuqing Yang (ORCID: https://orcid.org/0009-0007-7325-7981)
Institutions
- University of Illinois Urbana-Champaign (US)
- Sun Yat-sen University (CN)
- Dalian Institute of Chemical Physics (CN)
- Dalian Medical University (CN)
- Chinese Academy of Sciences (CN)
- Second Affiliated Hospital of Dalian Medical University (CN)
- Sun Yat-sen University Cancer Center (CN)
Publication Details
- Journal
- Signal Transduction and Targeted Therapy
- Published
- 2025-03-05
- DOI
- https://doi.org/10.1038/s41392-025-02159-1
- Citations
- 26
- Primary Topic
- Childhood Cancer Survivors' Quality of Life
- Type
- article
- Field-Weighted Citation Impact
- 90.85
Funders
- National Natural Science Foundation of China
- National Key Research and Development Program of China