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GP36: High Beta Integrin Expression is Differentially Associated with Worsened Pancreatic Ductal Adenocarcinoma Outcomes

Introduction: Outcomes in pancreatic ductal adenocarcinoma (PDAC) are known to be worse in tumors with high integrin β1 expression, but targeted monotherapy against this integrin has not been effective. Seven other beta integrins are expressed in mammalian biology and they are known to have overlapping and compensatory signaling in biological systems . However, their roles in PDAC are poorly understood and have not been systematically compared to integrin β1 biology.

Methods: We analyzed the clinical outcomes against beta integrin 1-8 (ITGB1-8) expression in PDAC samples from two large independent cohorts, The Cancer Genome Atlas (TCGA) and GSE21501. Biological function and tumor microenvironment composition were studied using Gene Set Enrichment Analysis and tumor microenvironment cell cybersorting via the xCell and MCP-counter algorithms.

Results: Expression of all eight beta integrins is significantly increased in PDACs relative to normal pancreatic tissues (all P<0.001). ITGB1, 2, 5, and 6 have similarly enriched gene patterns related to transforming growth factor (TGF)-β, epithelial mesenchymal transition, inflammation, stemness, and angiogenesis pathways. Homologous recombination defects and neoantigens are increased in high-ITGB4, 5, and 6 tumors, with decreased overall survival in high-ITGB1, 5, and 6 tumors compared to low expression tumors (hazard ratios 1.5-2.0). High-ITGB1, 2, and 5 tumors have increased fibroblast infiltration (all P<0.01) while endothelial cells are increased in high-ITGB2 and 3 tumors (all P<0.05). Overall, beta integrin expression does not correlate to immune cell populations in PDACs.

Conclusion: While all beta integrins are overexpressed in PDACs, they exert differential effects on PDAC biology. ITGB2, 5, and 6 have a similar profile to ITGB1, suggesting that future research in PDAC integrin therapy needs to consider the complementary signaling profiles mediated by these integrins.