Mol Oncol. 2026 Mar 1. doi: 10.1002/1878-0261.70218. Online ahead of print.
ABSTRACT
Transcriptional heterogeneity in pancreatic ductal adenocarcinoma (PDAC) arises not only from changes in gene expression but also from dynamic rewiring of gene-gene coordination. Using a divergent-edge framework applied to 77 155 malignant cells from 42 tumors, we identified four reproducible adaptive modules-integrated growth-energy (IGE), stress-adaptive transcription (SAT), IL-2-linked immune evasion (IL2), and multi-pathway collective invasion (MPC)-that cut across canonical PDAC states and reflect distinct regulatory programs. Integrating these modules with CRISPR-Cas9 dependency profiles and PRISM drug-response data revealed that adaptive behaviors collapse into two higher-order axes: a biosynthetic-metabolic IGE axis enriched for translational and DNA-repair dependencies, and a broader SAT-IL2-MPC stress-immune-invasion axis characterized by proteostasis, cytokine-linked, and cytoskeletal vulnerabilities. This architecture emerges only when divergent-edge modules are mapped into functional genomics space. Module activity also carried clinical relevance in PDAC. SAT-high tumors showed poorer survival, while MPC-high tumors exhibited a similar adverse trend; together, these modules defined a stress-immune-invasion poor-prognosis axis. In contrast, IGE activity showed no overall risk association, although an optimal-cut point-defined IGE-high subgroup displayed modestly improved survival.
PMID:41766370 | DOI:10.1002/1878-0261.70218
