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

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. This study aims to explore the mechanisms by which surgical techniques influence colorectal cancer liver metastasis (CRLM). The prognosis of a real-world cohort of 240 CRLM patients undergoing major and minor hepatectomy was compared after adjusting for confounders. To model CRLM, we induced liver metastasis in mice by transsplenically injecting MC38 cells. Cytometry by Time-Of-Flight, RNA sequencing, and untargeted metabolomics were used to explore how surgical choice affected CRLM prognosis. IHC was performed in another real-world cohort of 150 CRLM patients treated with hepatectomy to confirm the role of YAP1 signaling in CRLM progression. We found that CRLM patients and mice undergoing major hepatectomy had longer survival and lower recurrence rates compared to those undergoing minor hepatectomy. Mechanistically, extensive hepatectomy activated hepatocellular YAP1 by regulating epidermal growth factor receptor, altering glutamine metabolism genes, and increasing liver glutamine consumption. This metabolic shift led to glutamine scarcity in tumor cells, causing higher reactive oxygen species production, which inhibited YAP1 activity in tumor cells. Consequently, chemokine C-X-C motif chemokine ligand 5 (CXCL5) production decreased, reducing myeloid-derived suppressor cells (MDSCs) infiltration and enhancing CD8+ T cell immunological function. We propose that major hepatectomy may upregulate hepatocellular YAP1 activity while downregulating tumoral YAP1 activation through glutamine competition, which leads to reduced MDSCs infiltration in the tumor, thereby suppressing the growth and recurrence of CRLM.