Multi-omics analysis of polyamine metabolism implicates NT5E/CD73 in the progression of pancreatic cancer

Abstract

Pancreatic ductal adenocarcinoma (PDAC) exhibits profound metabolic reprogramming, with polyamine metabolism emerging as a key driver of tumor progression and immune evasion. However, its comprehensive role and clinical significance in PDAC remain largely unexplored. We performed an integrative analysis using bulk transcriptomics, single-cell RNA sequencing (scRNA-seq), and functional assays to systematically characterize polyamine metabolism in PDAC. A polyamine metabolism-based prognostic model (PMscore) was developed via principal component analysis, and key regulatory genes were identified using a random forest algorithm. Functional studies in vitro and in vivo assessed the role of NT5E (CD73), a core gene involved in polyamine metabolism, in tumor biology and the tumor microenvironment (TME). Polyamine metabolism was markedly upregulated in PDAC and associated with poor prognosis. The PMscore effectively stratified patients into three prognostic subgroups and was predictive of metabolic and immune features. NT5E was identified as a critical regulator, highly expressed in epithelial and mesenchymal cells. Its knockdown impaired polyamine metabolism, reduced tumor cell proliferation and migration, and altered TME composition. Notably, CD73⁺ cancer-associated fibroblasts (CAFs) were enriched near tumor cells, suggesting their involvement in metabolic crosstalk and immunosuppression. Our study provides a comprehensive multi-omics characterization of polyamine metabolism in PDAC. NT5E serves as a key metabolic and immunoregulatory gene, representing a promising biomarker and therapeutic target. Combined inhibition of NT5E and polyamine metabolism may offer a novel strategy to suppress tumor progression and modulate the immunosuppressive TME in PDAC.