Subset of STAT3 target genes induced by stress/inflammation defines poor survival for pancreatic cancer

STAT3 is a known oncogenic driver of pancreatic ductal adenocarcinoma (PDAC). Here we sought to define its specific role in coordinating adaptations to inflammation and stress within the tumor microenvironment critical for tumor progression. Exposing PDAC cells to hypoxia or the inflammatory cytokine oncostatin-M induced phospho-STAT3 binding to enhancer regions regulating 27 genes associated with poor survival. Among these, we confirmed STAT3-mediated upregulation of ITGB3 (integrin beta-3) facilitated tumor initiation and progression in mice, yet this adaptive response did not occur in certain cell lines with inherently closed chromatin at ITGB3 enhancer regions. By integrating ATAC-seq and ChIP-seq data for beta3-inducible vs. non-inducible cell lines, we identified an 18-gene signature reflecting a tumors ability to exploit STAT3 to overcome inflammation and stress, termed STAT3-receptive enhancers stratify severity (STRESS). The STRESS signature is distinct from previously defined molecular subtypes and is a stronger predictor of poor relapse-free survival for PDAC patients.