Gastro Hep Advances (Jan 2022)
Eicosanoids in the Pancreatic Tumor Microenvironment—A Multicellular, Multifaceted Progression
Abstract
Background and Aims: Eicosanoids, oxidized fatty acids that serve as cell-signaling molecules, have been broadly implicated in tumorigenesis. Here, we aimed to identify eicosanoids associated with pancreatic tumorigenesis and the cell types responsible for their synthesis. Methods: We profiled normal pancreas and pancreatic ductal adenocarcinoma in mouse models and patient samples using mass spectrometry. We interrogated RNA sequencing data sets for eicosanoid synthase or receptor expression. Findings were confirmed by immunostaining. Results: In murine models, we identified elevated levels of prostaglandin D2 (PGD2), prostacyclin, and thromboxanes in neoplasia while prostaglandin E2 (PGE2), 12-HHTre, HETEs, and HDoHEs are elevated specifically in tumors. Analysis of single-cell RNA sequencing data sets suggests that PGE2 and prostacyclins are derived from fibroblasts, PGD2, and thromboxanes from myeloid cells, and PGD2 and 5-HETE from tuft cells. In patient samples, we identified a transition from PGD2- to PGE2-producing enzymes in the epithelium during the transition to pancreatic ductal adenocarcinoma, fibroblast/tumor expression of PTGIS, and myeloid/tumor cell expression of TBXAS1. Conclusion: Our analyses identify key changes in eicosanoid species during pancreatic tumorigenesis and the cell types that contribute to their synthesis. Thromboxane and prostacyclin expression is conserved between animal models and human disease and may represent new druggable targets.
