2. Academic Validation
  3. Liver-breast communication of adipocyte-oriented exosomes drives primary mammary cancer progression

Liver-breast communication of adipocyte-oriented exosomes drives primary mammary cancer progression

  • Cell Metab. 2025 Sep 24:S1550-4131(25)00385-7. doi: 10.1016/j.cmet.2025.08.012.
Chunni Li 1,  Yiwen Lu 1,  Yihong Li 1,  Ting Liu 2,  Hong Deng 3,  Mingchao Gao 4,  Boxuan Zhou 5,  Jiayu Liu 1,  Junchao Cai 6,  Di Huang 1,  Linbin Yang 1,  Jin Jin 7,  Dongming Kuang 8,  Shicheng Su 9
Affiliations

Affiliations

  • 1 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
  • 2 School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.
  • 3 Department of Infectious Diseases, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
  • 4 Department of Urology, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China.
  • 5 Department of Breast Disease Center, the First Affiliated Hospital, Nanchang University, Nanchang 330006, China.
  • 6 Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China.
  • 7 Center for Neuroimmunology and Health Longevity, the Third Affiliated Hospital, Sun Yat-Sen University, Guangzhou 510630, China.
  • 8 Guangdong Province Key Laboratory of Pharmaceutical Functional Genes, MOE Key Laboratory of Gene Function and Regulation, School of Life Sciences, Sun Yat-Sen University, Guangzhou 510275, China.
  • 9 Guangdong Provincial Key Laboratory of Malignant Tumor Epigenetics and Gene Regulation, Medical Research Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Breast Tumor Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China; New Cornerstone Science Laboratory, Sun Yat-Sen University, Guangzhou 510080, China; Biotherapy Center, Sun Yat-Sen Memorial Hospital, Sun Yat-Sen University, Guangzhou 510120, China; Department of Immunology, Zhongshan School of Medicine, Sun Yat-Sen University, Guangzhou 510080, China; State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences, Beijing Institute of Lifeomics, Beijing 102200, China. Electronic address: sushch@mail.sysu.edu.cn.
PMID: 40997802 DOI: 10.1016/j.cmet.2025.08.012
Abstract

The incidence of certain types of extrahepatic cancers significantly increases in nonalcoholic fatty liver disease (NAFLD), the mechanisms of which are elusive. Here, we demonstrate that NAFLD is correlated with a higher risk of breast Cancer in individuals with atypical hyperplasia and poor prognosis in patients with breast Cancer. In mice, fatty liver exosomes are preferentially accumulated in adipocytes, and their enrichment in mammary adipocytes fosters a pro-tumor breast microenvironment. Adipocyte tropism is dictated by the binding of exosomal ErbB4 to neuregulin 4 (Nrg4). tRNA methyltransferase 10 homolog C (TRMT10C) in fatty liver exosomes translocates to mitochondria and inhibits Nd5 and Nd6 mRNA translation by inducing N1-methyladenosine modifications in adipocytes. ND5 and ND6 reduction increases Reactive Oxygen Species and consequently enhances free fatty acid release, which fuels tumor progression. Plasma ErbB4+ exosomes are an independent prognostic factor for patients with breast Cancer and comorbid NAFLD. Collectively, we reveal a liver-breast metabolic remote interaction that drives Cancer development.

Keywords

N(1) methyladenosine; adipocyte; breast cancer; exosome; nonalcoholic fatty liver disease.

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