Differential Expression of Polyamine Pathways in Human Pancreatic Tumor Progression and Effects of Polyamine Blockade on Tumor Microenvironment

SIMPLE SUMMARY: Pancreatic cancer has a five-year survival rate of less than 8% and is the fourth leading cause of cancer death in the United States. Existing therapeutics have failed to improve pancreatic ductal adenocarcinoma (PDAC) patient outcomes. There has been success with other tumor types in targeting aberrant polyamine upregulation as a therapeutic strategy. The present study identified dysregulation of polyamine pathways to be evident in human PDAC progression. Additionally, reduced survival of pancreatic cancer patients was associated with increased expression of specific polyamine-related genes. Polyamine blockade therapy significantly increased overall survival of pancreatic tumor-bearing mice, along with macrophage presence (F4/80) and significantly increased T-cell co-stimulatory marker (CD86) in the tumor microenvironment. Based on these findings, we hypothesized that a polyamine blockade therapy could potentially prime the tumor microenvironment to be more susceptible to existing therapeutics. Future studies which test polyamine blockade therapy with existing therapeutics could increase the molecular tools available to treat PDAC. ABSTRACT: Pancreatic cancer is the fourth leading cause of cancer death. Existing therapies only moderately improve pancreatic ductal adenocarcinoma (PDAC) patient prognosis. The present study investigates the importance of the polyamine metabolism in the pancreatic tumor microenvironment. Relative mRNA expression analysis identified differential expression of polyamine biosynthesis, homeostasis, and transport mediators in both pancreatic epithelial and stromal cells from low-grade pancreatic intraepithelial neoplasia (PanIN-1) or primary PDAC patient samples. We found dysregulated mRNA levels that encode for proteins associated with the polyamine pathway of PDAC tumors compared to early lesions. Next, bioinformatic databases were used to assess expression of select genes involved in polyamine metabolism and their impact on patient survival. Higher expression of pro-polyamine genes was associated with poor patient prognosis, supporting the use of a polyamine blockade therapy (PBT) strategy for inhibiting pancreatic tumor progression. Moreover, PBT treatment of syngeneic mice injected intra-pancreatic with PAN 02 tumor cells resulted in increased survival and decreased tumor weights of PDAC-bearing mice. Histological assessment of PBT-treated tumors revealed macrophage presence and significantly increased expression of CD86, a T cell co-stimulatory marker. Collectively, therapies which target polyamine metabolism can be used to disrupt tumor progression, modulate tumor microenvironment, and extend overall survival.