A STAT3/integrin axis accelerates pancreatic cancer initiation and progression

The signal transducer and activator of transcription 3 (STAT3) pathway drives pancreatic ductal adenocarcinoma (PDAC) progression by coordinating cellular responses to stress and inflammation. We perform ChIP-seq on hypoxia- or oncostatin-M-treated PDAC cells to identify sites at which phospho-STAT3 binds to regulate the expression of genes linked to poor survival. A top hit among these is ITGB3, which we show promotes PDAC initiation and progression. Single-cell transcriptomics reveal that ITGB3 expression is enriched in PDAC cells experiencing oxidative stress due to chemotherapy. Moreover, high ITGB3 expression positively correlates with STAT3 signaling, hypoxia, and the basal subtype. Mechanistically, chromatin accessibility at ITGB3 enhancers controls STAT3's ability to induce ITGB3 expression, illuminating a plastic regulatory mechanism modulating STAT3 activity. Leveraging this insight, we identify additional STAT3 target genes regulated similarly to ITGB3 to establish an 18-gene signature involved in adaptive responses and able to stratify survival outcomes. Collectively, these findings highlight a novel opportunity to stratify PDAC subpopulations for STAT3-targeted therapies.