Eicosanoids in the Pancreatic Tumor Microenvironment - a Multicellular, Multifaceted Progression

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 (PDAC) in mouse models and patient samples using mass spectrometry. We interrogated RNA sequencing datasets for eicosanoid synthase or receptor expression. Findings were confirmed by immunostaining.

Results: In murine models, we identified elevated levels of PGD, prostacyclin, and thromboxanes in neoplasia while PGE, 12-HHTre, HETEs, and HDoHEs are elevated specifically in tumors. Analysis of scRNA-seq datasets suggests that PGE and prostacyclins are derived from fibroblasts, PGD and thromboxanes from myeloid cells, and PGD and 5-HETE from tuft cells. In patient samples, we identified a transition from PGD to PGE-producing enzymes in the epithelium during the transition to PDAC, fibroblast/tumor expression of PTGIS, and myeloid/tumor cell expression of TBXAS1.

Conclusions: 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.