Stromal Annexin A2 expression is predictive of decreased survival in pancreatic cancer

Pancreatic ductal adenocarcinoma (PDA) is renowned for high rates of metastasis and poor survival. Its notoriously dense fibrotic stroma contributes to chemoresistance. Stromal signaling in PDA is recognized for its multiple roles in regulating tumor invasion and metastasis. However, no stromal biomarker which can predict survival in PDA exists. Annexin A2 (AnxA2) was formerly identified as a metastasis-associated protein in PDA and tumoral overexpression is associated with poor survival. In this study, we examined AnxA2 expression in the tumor microenvironment in a preclinical model of PDA which suggests its role in tumor colonization. We injected wild-type (KPC) and AnxA2 knockout (KPCA) pancreatic cells into C57BL/GJ (B6) and AnxA2 knockout (KO) mice using the hemi-spleen model and observed their survival. We performed quantitative immunohistochemistry examining stromal AnxA2 expression in 56 patients who had surgically resected PDA and correlated expression with clinical outcomes. B6 mice injected with KPC cells demonstrated decreased median survival compared to those injected with KPCA cells (90 days vs. not reached, p < 0.0001) whereas there was no survival difference in the AnxA2 KO mice (p = 0.63). In patient specimens, we found that high stromal AnxA2 expression (≥80th percentile) was associated with significantly reduced disease-free survival (p = 0.002) and overall survival (p < 0.001). Using multivariate Cox models, there were no significant associations between other clinical covariates apart from high stromal AnxA2 expression. This study highlights the role that stromal AnxA2 expression plays as a prognostic marker in PDA and its potential as a predictive biomarker for survival outcomes in PDA.