Key oxidized lipid metabolites in pancreatic cancer tissue and metastasis based on metabolomics analysis

Pancreatic cancer (PC) represents a highly lethal malignancy characterized by diagnostic challenges owing to nonspecific early symptoms and insufficiently sensitive biomarkers. This investigation sought to identify novel PC biomarkers through lipidomic profiling, an emerging metabolomics methodology examining lipid pathways in disease pathogenesis.

We established a humanized murine PC model. Small-molecule oxidized lipid metabolites in primary pancreatic tumors and hepatic metastases were quantitatively analyzed using liquid chromatography-tandem mass spectrometry (LC-MS/MS) integrated with a comprehensive metabolomics platform. Multivariate statistical approaches including principal component analysis (PCA) and orthogonal partial least squares-discriminant analysis (OPLS-DA) were systematically applied.

Analysis identified 64 differentially expressed oxidized lipids structurally classified as unsaturated fatty acid derivatives. Comparative assessment of metabolic profiles revealed a pronounced reduction in prostaglandins (PGE₂, PGD₂) within hepatic metastases of autotaxin (ATX)-knockout models, indicating their functional involvement in metastatic progression via the ATX-lysophosphatidic acid (LPA) signaling axis. KEGG pathway enrichment analysis demonstrated statistically significant perturbations in linolenic acid (LA) metabolism between NC-PC and KAI1-PC cohorts (20 altered metabolites). Notably, upregulation of the oxidized lipid mediator 12(13)-EpOME functionally contributed to KAI1/CD82-mediated metastasis suppression.

Our findings establish prostaglandins PGE₂/PGD₂ as promotors of PC hepatic metastasis through ATX-LPA axis activation. The lipid metabolite 12(13)-EpOME emerges as both a mechanistic effector in KAI1/CD82-dependent metastasis inhibition and a promising candidate biomarker for early PC detection, suggesting novel diagnostic and therapeutic strategies.