Metabolic, transcriptomic, and proteomic adaptations in pancreatic ductal adenocarcinoma-patient derived xenograft models across serial passages

作者：Pengfei Guo, Haizong Fang, Han Shi, Junrong Zhang, Ge Song, Chongjiu Fan, Xinyu Qiu, Xianchao Lin, Wen Shi, Jianghua Feng, Heguang Huang, Tianhong Teng · 发表于：Journal of Translational Medicine · 年份：2025 · DOI：10.1186/s12967-025-06787-7 · 被引用次数：4 · 研究领域：Cancer, Hypoxia, and Metabolism、Pancreatic and Hepatic Oncology Research、Cancer Research and Treatments

BACKGROUND: Patient-derived xenograft (PDX) models are crucial for tumor biology and therapeutic response evaluations. The metabolic, transcriptomic, and proteomic changes in PDX models derived from pancreatic ductal adenocarcinoma (PDAC) during serial passaging remain poorly understood. METHODS: H NMR spectroscopy. Multi-generational PDX models (P1-P3) from six patients were analyzed for molecular characteristics. Transcriptomic and proteomic analyses were performed using RNA-seq and 4D-DIA mass spectrometry, identifying differentially expressed genes (DEGs) and proteins, which were then subjected to enrichment analysis to uncover key biological functions. A gene-protein interaction network was constructed to identify functional modules across passages. RESULTS: PDX tumors closely mirrored primary tumors in metabolic characteristics, maintaining key metabolic features of PDAC with minor variations in amino acid metabolism, particularly glutamine and aspartate levels. PDX-2 and PDX-3 showed dysregulation in aminoacyl-tRNA biosynthesis and glycine, serine, and threonine metabolism. DEGs progressively increased across passages, with later-generation PDX models exhibiting transcriptional dysregulation, including enhanced MAPK signaling activity and reduced immune-related pathway expression. Proteomic analysis identified five consistently altered proteins (ZDHHC20, ZNF644, GNL2, PDGFRB, INO80E), indicative of enhanced signal transduction, cell cycle regulation, and DNA repair. Ge...