GP73-dependent regulation of exosome biogenesis promotes colorectal cancer liver metastasis
Linfei Huang, Wei Meng, Huilong Li, Mingxin Yu, Luming Wan, Ruzhou Zhao, Qi Gao, Lijuan Sun, Xufeng Hou, Yunhai Mo, Qing Huang, Lan Zhen, Xiaopan Yang, Jingfei Li, Nan Wang, Chun‐Dong Zhang, He Jin, Li Zhou, Yixin Xu, Haotian Lin, Xuhui Zhang, Boan Li, Yue Han, Jing Yuan, Rui Zhang, Feixiang Wu, Hui Zhong, Congwen Wei
Abstract
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.