Stage-resolved gene drivers of pancreatic ductal adenocarcinoma progression and therapeutic vulnerabilities

Pancreatic ductal adenocarcinoma shows early dissemination, stromal remodeling, and therapy resistance, but how tumor programs co-evolve with immune and stromal changes across stages remains unclear. We built a stage-resolved transcriptomic atlas using bulk RNA sequencing of FFPE samples from 443 untreated tumors spanning resectable, locally advanced, primary metastatic, and liver metastatic disease. Integrative modeling identified ten transcriptional programs with monotonic dynamics during progression. Early stages were enriched for epithelial differentiation and immune-stimulatory signals. Advanced stages showed increased cytoskeletal remodeling, vesicular trafficking, oxidative stress responses, and mitochondrial metabolism. Pathway analysis revealed enhanced PI3K-AKT-mTOR signaling and MYC target engagement in metastatic disease. Immune deconvolution showed loss of CD8⁺ T cells, dendritic cells, and M1 macrophages. Compact gene signatures stratified stage and survival and generalized to TCGA and ICGC cohorts. Functional assays confirmed greater invasiveness, altered redox balance, and mitochondrial dependence in advanced disease, suggesting stage-associated metabolic vulnerabilities.