Extracellular vesicles from chemotherapy-induced senescent tumor cells reprogram hepatic phospholipid metabolism to promote pancreatic cancer liver metastasis

BACKGROUND: Pancreatic ductal adenocarcinoma (PDAC) is a highly metastatic disease, with over one-third of patients developing liver metastasis following neoadjuvant chemotherapy (NAC). This study aimed to investigate how the effect of chemotherapy on the primary tumor shapes the hepatic pre-metastatic niches (PMNs), which remains poorly understood. METHODS: RNA sequencing was performed in a PDAC cohort to identify transcriptomic features associated with metastasis. We employed orthotopic and liver metastatic tumor models in mice to investigate the effects of extracellular vesicles derived from chemotherapy-treated PDAC cells, referred to as senescence-associated extracellular vesicles (S-EVs), on the hepatic PMNs. Mechanistically, we integrated proteomics and metabolomics to elucidate the molecular mechanisms by which S-EVs mediate hepatic metabolic reprogramming. Further, we utilized hepatocyte-specific Ache-knockout mice to validate the molecular mechanisms through which S-EVs promote liver metastasis in vivo. RESULTS: Chemotherapy-induced senescence in primary tumors correlated with PDAC liver metastasis and poor prognosis. S-EVs facilitated PMNs formation by promoting hepatic phosphatidylcholine (PC) accumulation. Mechanistically, S-EV-delivered hnRNPA1 stabilized AChE mRNA, thereby driving PC accumulation in the liver. In vitro co-culture system, PC depletion in hepatocytes successfully restored the impaired cytotoxicity of CD8⁺ T cells caused by S-EVs. Consistently, hepatocyte-specific Ache ablation in vivo restored S-EV-impaired CD8⁺ T cells cytotoxicity. Inhibition of AChE with pyridostigmine remodeled the hepatic PMNs and suppressed liver metastasis. CONCLUSIONS: S-EVs from chemotherapy-induced senescent PDAC cells reshaped hepatic PMNs through AChE-dependent PC accumulation, thereby impairing CD8⁺ T cell cytotoxicity and promoting PDAC liver metastasis. Targeting AChE with pyridostigmine represented a promising strategy to prevent metastasis and augment the therapeutic efficacy of NAC.