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<p>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.</p>

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GP73-dependent regulation of exosome biogenesis promotes colorectal cancer liver metastasis

  • 期刊论文

  • 出版模式：

    开放获取

  • 发表日期：

    2025年5月26日

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  • Linfei Huang,
  • Meng Wei,
  • 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,
  • Chundong Zhang,
  • Haoran Jin,
  • Li Zhou,
  • Yixin Xu,
  • Haotian Lin,
  • Xuhui Zhang,
  • Boan Li,
  • Yue Han,
  • Jing Yuan,
  • Rui Zhang,
  • Feixiang Wu,
  • Hui Zhong,
  • Congwen Wei

摘要

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.