Extracellular vesicle-induced lipid dysregulation drives liver premetastatic niche formation in colorectal cancer

BACKGROUND: Liver metastasis is a major cause of mortality in patients with colorectal cancer (CRC). Understanding how CRC cells influence the formation of hepatic premetastatic niches (PMNs) is crucial for developing targeted therapies. OBJECTIVE: We aimed to elucidate the underlying mechanism by which extracellular vesicles (EVs) derived from CRC cells with high liver metastatic capacity facilitate the formation of hepatic PMNs. DESIGN: CRC cells with high metastatic potential were selected using a liver metastasis mouse model through two rounds of splenic injections. The role of EVs secreted by CRC cells in the liver was investigated using lipidomics and single-cell sequencing. Clinical significance was evaluated by tumour samples from patients with CRC. RESULTS: EVs derived from highly metastatic CRC cells facilitate the formation of PMNs by driving hepatic lipid accumulation. The upregulation of fatty acid (FA) synthesis in CRC cells leads to significantly increased levels of prosteatogenic lipids in EVs, promoting hepatic lipid accumulation. Inhibition of hepatic lipid accumulation reduces the prometastatic capability of EVs secreted by highly metastatic CRC cells. Moreover, EVs are primarily taken up by Kupffer cells, where they induce tumour necrosis factor alpha secretion, further driving hepatic lipid accumulation. In patients with late-stage CRC, CRC cells exhibit elevated FA synthesis, which contributes to hepatic lipid accumulation. Notably, suppressing FA synthesis in CRC patient-derived organoids alleviates hepatic lipid accumulation and reduces liver metastasis. CONCLUSION: Inhibition of FA synthesis in CRC cells with high metastatic potential reduces hepatic lipid accumulation and subsequent metastasis, highlighting a new strategy for preventing liver metastasis.