Zhang Enkui, Ding Xinjia, Zhang Jixin, Liu Weikang, Liu Guangnian, Li Mingzhe, Liu Xinxin, Wang Yingjin, Zhang Fusheng, Li Baoyi, Zhu Yu, Yan Yupeng, Liu Jiayu, Wang Yuxin, Tian Xiaodong, Ma Yongsu, Yang Yinmo
Department of Hepatobiliary and Pancreatic Surgery, Peking University First Hospital, Beijing, 100034, China.
Department of Medical Oncology, Peking University First Hospital, Beijing, 100034, China.
Cancer Lett. 2025 Oct 10;630:217887. doi: 10.1016/j.canlet.2025.217887. Epub 2025 Jun 27.
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.
胰腺导管腺癌（PDAC）表现出深刻的代谢重编程，多胺代谢成为肿瘤进展和免疫逃逸的关键驱动因素。然而，其在PDAC中的全面作用和临床意义仍 largely unexplored。我们使用批量转录组学、单细胞RNA测序（scRNA-seq）和功能测定进行了综合分析，以系统地表征PDAC中的多胺代谢。通过主成分分析开发了基于多胺代谢的预后模型（PMscore），并使用随机森林算法鉴定了关键调控基因。体外和体内功能研究评估了参与多胺代谢的核心基因NT5E（CD73）在肿瘤生物学和肿瘤微环境（TME）中的作用。多胺代谢在PDAC中明显上调，并与预后不良相关。PMscore有效地将患者分为三个预后亚组，并可预测代谢和免疫特征。NT5E被鉴定为关键调节因子，在上皮细胞和间充质细胞中高度表达。其敲低损害了多胺代谢，减少了肿瘤细胞的增殖和迁移，并改变了TME组成。值得注意的是，CD73癌相关成纤维细胞（CAFs）在肿瘤细胞附近富集，表明它们参与代谢串扰和免疫抑制。我们的研究提供了PDAC中多胺代谢的全面多组学特征。NT5E作为关键的代谢和免疫调节基因，代表了一个有前景的生物标志物和治疗靶点。联合抑制NT5E和多胺代谢可能提供一种新策略来抑制PDAC中的肿瘤进展并调节免疫抑制性TME。
