Eicosanoids in the pancreatic tumor microenvironment – a multicellular, multifaceted progression

ABSTRACT Eicosanoids, oxidized fatty acids that serve as cell-signaling molecules, have been broadly implicated in tumorigenesis. To identify eicosanoids relevant to pancreatic tumorigenesis, 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. In murine models, we identified elevated levels of PGD 2 , prostacyclin, and thromboxanes in neoplasia while PGE 2 , 12-HHTre, HETEs, and HDoHEs are elevated specifically in tumors. Analysis of scRNA-seq datasets suggests that PGE 2 and prostacyclins are derived from fibroblasts, PGD 2 and thromboxanes from myeloid cells, and PGD 2 and 5-HETE from tuft cells. In patient samples, we identified a transition from PGD 2 to PGE 2 -producing enzymes in the epithelium during the transition to PDAC, fibroblast/tumor expression of PTGIS, and myeloid/tumor cell expression of TBXAS1. Altogether, our analyses identify key changes in eicosanoid species during pancreatic tumorigenesis and the cell types responsible for their synthesis.