Liver regeneration-associated hepatocellular YAP1 activation prevents colorectal cancer liver metastasis through glutamine competition

  • Sci Adv. 2025 Aug 22;11(34):eadw6926. doi: 10.1126/sciadv.adw6926.
Qiang Yu  1 ,  Mincheng Yu  1 ,  Peiyi Xie  1 ,  Lei Guo  1 ,  Yufei Zhao  1 ,  Wenxin Xu  1 ,  Xian Li  1 ,  Mengyuan Wu  2 ,  Zihao Zhang  3 ,  Zheng Chen  1 ,  Yongsheng Xiao  1 ,  Jian Zhou  1 ,  Jia Fan  1 ,  Mien-Chie Hung  4 ,  Yongfeng Xu  1 ,  Bo Zhang  1 ,  Qinghai Ye  1 ,  Hui Li  1  5
Affiliations
  • 1. Department of Hepatobiliary Surgery and Liver Transplantation, Liver Cancer Institute, Zhongshan Hospital, Fudan University, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Shanghai 200032, P.R. China.
  • 2. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
  • 3. Department of Gastrointestinal Surgery, Zhongshan Hospital, Fudan University, Shanghai 200032, P.R. China.
  • 4. Graduate Institute of Biomedical Sciences, Research Center for Cancer Biology, and Center for Molecular Medicine, China Medical University, Taichung 404, Taiwan.
  • 5. Department of Liver Surgery, Zhongshan Hospital (Xiamen Branch), Fudan University, Xiamen 361015, P.R. China.
PMID: 40845109 DOI: 10.1126/sciadv.adw6926
Abstract

The literature suggests that hepatocellular Yes-associated protein 1 (YAP1) signaling is activated following hepatectomy and that such activation can suppress the growth of metastatic liver tumors. The prognosis of a real-world cohort of 240 patients with colorectal Cancer liver metastasis (CRLM) undergoing major and minor hepatectomy was compared after adjusting for confounding factors. To model CRLM, we induced liver metastasis in mice by transsplenically injecting MC38 cells. We found that patients with CRLM and mice undergoing major hepatectomy had better survival compared to those undergoing minor hepatectomy. Mechanistically, extensive hepatectomy activates hepatocellular YAP1 by regulating the epidermal growth factor receptor, altering glutamine metabolism-related gene expression and increasing liver glutamine consumption. This metabolic shift leads to glutamine scarcity in tumor cells, causing increased Reactive Oxygen Species production, which promotes loss of YAP1 activity in tumor cells. Consequently, the production of the chemokine CXCL5 is suppressed, which inhibits myeloid-derived suppressor cell infiltration and enhancing the immunological function of CD8+ T cells.

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