Aberrant CPS1 expression is linked to metabolic alterations and metastatic phenotypes in colorectal cancer liver metastasis

Abstract

Colorectal carcinoma liver metastasis (CRLM) is the main cause of mortality in colorectal cancer (CRC), yet its metabolic drivers remain poorly understood. Here, we integrated three GEO datasets to identify metabolic reprogramming signatures distinguishing CRLM compared to primary tumors. A four-gene metabolism-related risk model was constructed using LASSO-Cox regression in the TCGA M1 cohort and independently validated in GSE17536. Carbamoyl-phosphate synthase 1 (CPS1) emerged as an independent prognostic factor and was markedly upregulated in CRLM tissues compared with matched primary tumors and normal colon, as validated by immunohistochemistry and qRT-PCR in seven paired clinical specimens. Reciprocal loss- and gain-of function experiments in HCT116 and SW480 cells demonstrate that CPS1 promotes invasion and migration without affecting proliferation. Mechanistically, CPS1 exerted pro-metastatic effects independently of canonical urea cycle activity. Instead, CPS1 positively correlated with ether lipid metabolism, reciprocally regulating key enzymes including AGPS and modulating cadherin expression to enhance cellular plasticity. These finding reveal a previously unrecognized role of CPS1 in promoting CRLM via ether lipid metabolic remodeling, highlighting its potential as a prognostic biomarker and therapeutic target.