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Using a divergent\u2010edge framework applied to 77\u2009155 malignant cells from 42 tumors, we identified four reproducible adaptive modules\u2014integrated growth\u2010energy (IGE), stress\u2010adaptive transcription (SAT), IL\u20102\u2010linked immune evasion (IL2), and multi\u2010pathway collective invasion (MPC)\u2014that cut across canonical PDAC states and reflect distinct regulatory programs. Integrating these modules with CRISPR\u2013Cas9 dependency profiles and PRISM drug\u2010response data revealed that adaptive behaviors collapse into two higher\u2010order axes: a biosynthetic\u2013metabolic IGE axis enriched for translational and DNA\u2010repair dependencies, and a broader SAT\u2013IL2\u2013MPC stress\u2013immune\u2013invasion axis characterized by proteostasis, cytokine\u2010linked, and cytoskeletal vulnerabilities. This architecture emerges only when divergent\u2010edge modules are mapped into functional genomics space. Module activity also carried clinical relevance in PDAC. SAT\u2010high tumors showed poorer survival, while MPC\u2010high tumors exhibited a similar adverse trend; together, these modules defined a stress\u2013immune\u2013invasion poor\u2010prognosis axis. In contrast, IGE activity showed no overall risk association, although an optimal\u2010cut point\u2013defined IGE\u2010high subgroup displayed modestly improved survival.<\/jats:p>","DOI":"10.1002\/1878-0261.70218","type":"journal-article","created":{"date-parts":[[2026,3,8]],"date-time":"2026-03-08T17:00:31Z","timestamp":1772989231000},"page":"1857-1876","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Network divergence analysis identifies adaptive gene modules and two orthogonal vulnerability axes in pancreatic cancer"],"prefix":"10.1002","volume":"20","author":[{"given":"Brian","family":"Nelson","sequence":"first","affiliation":[{"name":"Department of Applied Mathematics and Statistics Stony Brook University  New York NY USA"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Lyanne","family":"Delgado\u2010Coka","sequence":"additional","affiliation":[{"name":"Department of Pathology Stony Brook 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