PLAAT2 facilitates the development of pancreatic cancer and serves as a predictor of resistance to chemotherapy.

[BACKGROUND] Pancreatic cancer (PC) remains one of the deadliest human malignancies, and reliable biomarkers for prognosis and therapeutic stratification are still lacking. PLAAT2 (phospholipase A and acyltransferase 2), an enzyme linked to lipid metabolism, has been implicated in metabolic regulation, but its role in PC is not fully defined.

[METHODS] Transcriptomic profiles from TCGA-PAAD and independent GEO datasets, together with the corresponding clinical annotations, were analysed to clarify the prognostic relevance and biological roles of PLAAT2. Functional enrichment, immune-cell infiltration, mutational profiles and predicted drug responses were analyzed, and a PLAAT2-related prognostic signature was generated by LASSO-Cox analysis and validated in external GEO datasets. In parallel, PLAAT2 expression was examined in paired PC tissues and matched non-cancerous counterparts by immunohistochemistry (IHC) and quantitative RT-PCR. The effects of PLAAT2 silencing on proliferation, migration, invasion and oxaliplatin sensitivity were evaluated in MiaPaCa-2 and CFPAC-1 cells.

[RESULTS] PLAAT2 levels were substantially higher in PC specimens, and tumours with high PLAAT2 expression tended to exhibit more advanced grade and stage together with poorer survival. High PLAAT2 expression was enriched in lipid-metabolic pathways and linked to an immune-dysregulated microenvironment characterized by reduced CD8⁺ T-cell infiltration and increased macrophages. The PLAAT2-high cohort also exhibited a higher frequency of somatic mutations, particularly in KRAS and TP53. An 11-gene PLAAT2-related signature stratified patients into distinct risk groups; high-risk patients showed significantly worse survival and lower predicted sensitivity to irinotecan, olaparib and oxaliplatin, and these findings were consistently validated in independent GEO cohorts. In an institutional cohort of 15 paired clinical samples, IHC and qRT-PCR confirmed higher PLAAT2 expression in tumor tissues than in adjacent non-tumor tissues. Functionally, PLAAT2 knockdown in MiaPaCa-2 and CFPAC-1 cells suppressed cell growth, migration and invasion and significantly enhanced the growth-inhibitory effect of oxaliplatin, accompanied by reduced IC₅₀ values.

[CONCLUSION] Collectively, these data support an oncogenic role of PLAAT2 in PC and indicate that PLAAT2 and its associated transcriptional signature may serve as potential biomarkers of prognosis and chemotherapeutic response, as well as candidate targets for precision therapy in PC.