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

Area of Science:

• Lipid mediators and cell signaling in cancer biology.
• Molecular mechanisms of pancreatic ductal adenocarcinoma (PDAC).

Background:

• Eicosanoids, oxidized fatty acids acting as cell-signaling molecules, are implicated in cancer development.
• Pancreatic ductal adenocarcinoma (PDAC) is a significant health concern with complex underlying molecular pathways.

Purpose of the Study:

• To identify eicosanoids associated with pancreatic tumorigenesis.
• To determine the specific cell types responsible for eicosanoid synthesis during PDAC development.

Main Methods:

• Mass spectrometry profiling of normal pancreas and PDAC in mouse models and human samples.
• Analysis of RNA sequencing data for eicosanoid synthase and receptor expression.
• Immunostaining to confirm findings.

Main Results:

• Elevated levels of PGD2, prostacyclin, and thromboxanes in neoplastic tissues; PGE2, 12-HHT, HETEs, and HDoHEs elevated in tumors.
• PGE2 and prostacyclins identified as fibroblast-derived; PGD2 and thromboxanes from myeloid cells; PGD2 and 5-HETE from tuft cells.
• Human PDAC samples show a shift from PGD2 to PGE2 production in the epithelium, with specific gene expression patterns in fibroblasts and myeloid cells.

Conclusions:

• Key changes in eicosanoid profiles occur during pancreatic tumorigenesis.
• Cell-specific synthesis of eicosanoids contributes to PDAC.
• Thromboxane and prostacyclin expression are conserved between models and humans, suggesting potential therapeutic targets.