High Mesothelin expression in pancreatic adenocarcinoma is associated with aggressive tumor features but not prognosis.

Mesothelin is a cell surface marker expressed on most pancreatic cancers and has been associated with aggressive biology. Despite its popularity as a drug target, clinical relevance of Mesothelin expression in pancreatic cancer is unclear. We set out to define transcriptomic signatures associated with high Mesothelin expression and identify its role in tumor biology and its clinical relevance. We analyzed pancreatic adenocarcinomas in the cancer genome atlas (TCGA), (n = 145) and the results were validated using GSE62452 cohort (n = 69). We divided the cohorts into high and low Mesothelin expression by the median. High Mesothelin was not associated with progression-free, disease-free, disease specific, nor overall survival in TCGA cohort. Despite this, high Mesothelin expression was associated with high Ki67 expression and enriched all five cell proliferation-related Hallmark gene sets, but not with previously investigated pathways: TNF-alpha, PI3K, nor angiogenesis. Mesothelin expression did not correlate with MUC16 expression. The high Mesothelin pancreatic cancers demonstrated higher homologous recombination deficiency, fraction altered, and silent and non-silent mutation rates (all P < 0.001) that indicate aggressive cancer biology. However, lymphocyte infiltration score, TIL regional fraction, TCR richness, infiltration of CD8 T-cells, and cytolytic activity were all significantly lower in Mesothelin high tumors (all P < 0.015). Finally, we found that Mesothelin expression significantly correlated with sensitivity to cytotoxic chemotherapy in pancreatic cancer cell lines. In conclusion, high Mesothelin expression is associated with enhanced proliferation, depressed immune response, and sensitivity to cytotoxic chemotherapy, which may explain there was no difference in survival in pancreatic cancer patients.