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  3. Gut dysbiosis conveys psychological stress to activate LRP5/β-catenin pathway promoting cancer stemness

Gut dysbiosis conveys psychological stress to activate LRP5/β-catenin pathway promoting cancer stemness

  • Signal Transduct Target Ther. 2025 Mar 5;10(1):79. doi: 10.1038/s41392-025-02159-1.
Bai Cui # 1,  Huandong Luo # 1 2,  Bin He # 1,  Xinyu Liu # 3,  Dekang Lv # 1,  Xiaoyu Zhang 1,  Keyu Su 1,  Sijia Zheng 3,  Jinxin Lu 1,  Cenxin Wang 1,  Yuqing Yang 1,  Zhuoran Zhao 1,  Xianxian Liu 1,  Xu Wang 1,  Yingrui Zhao 1,  Xiaoshan Nie 1,  Yuanyuan Jiang 1,  Ziyu Zhang 1,  Congcong Liu 1,  Xinyi Chen 1,  Anqi Cai 1,  Zhumeng Lv 1,  Zhihang Liu 1,  Fan An 1,  Yunkun Zhang 4,  Qiulong Yan 5,  Keith W Kelley 6,  Guowang Xu 3,  Lingzhi Xu 7,  Quentin Liu 8 9,  Fei Peng 10
Affiliations

Affiliations

  • 1 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China.
  • 2 State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China.
  • 3 Key Laboratory of Separation Sciences for Analytical Chemistry, National Chromatographic R&A Center, Dalian Institute of Chemical Physics, Chinese Academy of Sciences (CAS), Dalian, China.
  • 4 Department of Pathology, The Second Hospital of Dalian Medical University, Dalian, China.
  • 5 Department of Microbiology, College of Basic Medical Sciences, Dalian Medical University, Dalian, China.
  • 6 Department of Pathology, College of Medicine and Department of Animal Sciences, College of ACES, University of Illinois at Urbana-Champaign, Urbana, IL, USA.
  • 7 Department of Oncology, the Second Affiliated Hospital, Dalian Medical University, Dalian, China. xvlingzhi@sina.com.
  • 8 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. liuq9@mail.sysu.edu.cn.
  • 9 State Key Laboratory of Oncology in South China, Cancer Center, Sun Yat-sen University, Guangzhou, China. liuq9@mail.sysu.edu.cn.
  • 10 Institute of Cancer Stem Cell, Dalian Medical University, Dalian, China. pengfei@dmu.edu.cn.
  • # Contributed equally.
PMID: 40038255 DOI: 10.1038/s41392-025-02159-1
Abstract

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.

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