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.