Cancer-associated adipocytes promote peritoneal metastasis of colorectal signet ring cell carcinoma via FABP4 induction.

BACKGROUND

Colorectal signet ring cell carcinoma (SRCC) is a rare and aggressive subtype with a high propensity for peritoneal metastasis, yet the underlying mechanisms remain poorly understood.

METHODS

We isolated cancer-associated adipocytes (CAAs) from omental tissue adjacent to SRCC peritoneal metastases and examined their morphological and metabolic features compared to normal adipocytes (NAs). Co-culture systems, patient-derived organoids (PDOs), transcriptomic/metabolomic profiling, and peritoneal metastasis mouse models were employed to assess the functional impact of CAAs. The role of fatty acid binding protein 4 (FABP4) and its regulation via CAA-derived exosomes was also investigated.

RESULTS

CAAs exhibited a dedifferentiated phenotype, enhanced free fatty acid secretion, and upregulation of matrix metalloproteinases. Co-culture with CAAs significantly promoted SRCC PDO proliferation, stemness, and peritoneal metastasis, accompanied by a metabolic shift toward fatty acid utilization. Among fatty acid metabolism-related genes, FABP4 was markedly upregulated in peritoneal metastases and associated with poor prognosis. Functional assays confirmed that FABP4 promoted fatty acid oxidation (FAO), stemness, and metastasis in PDOs, while FABP4 knockdown abrogated these effects. Mechanistically, CAA-derived exosomes induced FABP4 expression in PDOs, and inhibition of exosome release reversed the pro-tumorigenic phenotypes.

CONCLUSIONS

CAA-derived exosomal signaling promotes SRCC aggressiveness through FABP4-mediated fatty acid metabolic reprogramming, identifying FABP4 as a potential therapeutic target for peritoneal metastasis in colorectal SRCC.