Immunohistochemical analysis and scRNA-Seq identifies vascular endothelial CXCR4 expression as a predictor of poor prognosis in pancreatic ductal adenocarcinoma

BACKGROUND: The clinical significance of C-X-C chemokine receptor 4 (CXCR4) expression at the invasive front of pancreatic ductal adenocarcinoma (PDAC) remains unclear. This study investigated CXCR4 expression in the vascular endothelium at sites of cancer tissue infiltration into the pancreatic surrounding fatty tissue in resected PDAC specimens. METHODS: We prepared tissue microarrays from 80 cases of PDAC resected between 2011 and 2023 and retrospectively analyzed the samples by immunohistochemistry. CXCR4 expression in blood vessels was semi-quantitatively scored (0 to 3+) and categorized as high (2-3+) or low (0-1+). We also analyzed the clinicopathological features associated with CXCR4 expression. Finally, leveraging public databases for single-cell RNA sequencing was used to confirm the localization of CXCR4 expression. RESULTS: Of the 80 cases, 33 exhibited high CXCR4 expression and 47 showed low expression. The high expression group had a significantly shorter median overall survival (469 versus 1176 days, P = 0.0361). In the multivariate analysis, high CXCR4 expression (hazard ratio 1.8180, 95% confidence interval, 1.0350-3.193, P = 0.0342) was an independent prognostic factor. single-cell RNA sequencing revealed sparse CXCR4 expression in arteries, veins, capillaries, and tip-like endothelial cells. CONCLUSION: Vascular endothelial CXCR4 expression at the invasive front of PDAC is associated with poor prognosis and may be associated with tumor progression in correlation with angiogenic mechanisms.