GP73-dependent regulation of exosome biogenesis promotes colorectal cancer liver metastasis
Colorectal cancer (CRC) liver metastasis is the main cause of cancer-related mortality. How liver influences intercellular communication to support CRC liver metastasis remains unknown. Herein, we link GP73, whose chronic upregulation in hepatocytes triggers non-obese metabolic-dysfunction associated steatotic liver disease (MASLD) in mice, with exosome biogenesis and CRC liver metastasis. Mice with high liver GP73 expression exhibited increased CRC liver metastasis in an exosome-dependent manner. GP73 modulated the cholesterol contents in endosomal compartments to promote exosome production. Quantitative proteomics revealed GP73 reshaped hepatocyte exosomal proteome and produced NAV2-rich exosomes. Clinically, serum GP73 levels positively correlated with exosomal NAV2 levels in CRC patients with liver metastasis. Knockdown of liver NAV2 suppressed enhanced CRC liver metastasis in GP73-induced non-obese mice, and GP73 blockade mitigated the increased CRC liver metastasis in obese mice fed by high-fat diet or high-fructose diet. Our findings suggest GP73 blockade as a potential therapeutic strategy for mitigating CRC liver metastasis.
Authors
- Xuhui Zhang (ORCID: https://orcid.org/0000-0003-3202-1159)
- Linfei Huang
- Mingxin Yu (ORCID: https://orcid.org/0000-0001-8823-0852)
- Yunhai Mo
- Xiaopan Yang (ORCID: https://orcid.org/0000-0003-1442-6179)
- Xufeng Hou (ORCID: https://orcid.org/0000-0001-5893-308X)
- Lijuan Sun (ORCID: https://orcid.org/0000-0003-3265-3893)
- He Jin (ORCID: https://orcid.org/0000-0001-7574-3018)
- Qi Gao (ORCID: https://orcid.org/0000-0002-2532-0997)
- Feixiang Wu (ORCID: https://orcid.org/0000-0001-6868-2181)
- Ruzhou Zhao
- Hui Zhong (ORCID: https://orcid.org/0000-0002-8996-0774)
- Haotian Lin (ORCID: https://orcid.org/0000-0003-4672-9721)
- Jingfei Li
- Chun‐Dong Zhang (ORCID: https://orcid.org/0000-0003-1804-1356)
- Congwen Wei (ORCID: https://orcid.org/0000-0002-3966-5507)
- Luming Wan (ORCID: https://orcid.org/0000-0002-0698-4077)
- Lan Zhen
- Li Zhou (ORCID: https://orcid.org/0000-0003-1945-3491)
- Boan Li (ORCID: https://orcid.org/0000-0002-2264-9295)
- Nan Wang (ORCID: https://orcid.org/0000-0003-1743-3585)
- Wei Meng (ORCID: https://orcid.org/0000-0001-5451-3125)
- Rui Zhang (ORCID: https://orcid.org/0000-0003-3335-0931)
- Jing Yuan (ORCID: https://orcid.org/0000-0003-4218-8462)
- Yue Han (ORCID: https://orcid.org/0000-0002-7395-7095)
- Qing Huang (ORCID: https://orcid.org/0000-0001-8393-2003)
- Huilong Li (ORCID: https://orcid.org/0009-0007-0192-0692)
- Yixin Xu
Institutions
- Changzhi University (CN)
- Guangxi Medical University (CN)
- Changzhi Medical College (CN)
- Chinese Academy of Medical Sciences & Peking Union Medical College (CN)
- Chinese PLA General Hospital (CN)
- National Cancer Center (US)
- National Clinical Research Center for Digestive Diseases (CN)
- Beijing Biocytogen (China) (CN)
- Fourth Affiliated Hospital of China Medical University (CN)
- Czech Academy of Sciences, Institute of Biotechnology (CZ)
- Capital Institute of Pediatrics (CN)
- Zhong Ke San Huan (China) (CN)
- Children's Hospital of Capital Institute of Pediatrics (CN)
- Liaoning Cancer Hospital & Institute (CN)
- China Medical University (CN)
Publication Details
- Journal
- Molecular Cancer
- Published
- 2025-05-25
- DOI
- https://doi.org/10.1186/s12943-025-02350-6
- Citations
- 10
- Primary Topic
- Extracellular vesicles in disease
- Type
- article
- Field-Weighted Citation Impact
- 8.06
Funders
- National Natural Science Foundation of China
- Guangxi Medical University
- Beijing Nova Program