S297 Altered Bioactive Lipid Signaling Leading to Increased Risk of Pancreatic and Lung Cancers in Cystic Fibrosis

Introduction: Lipid dysregulation involving eicosanoids and specialized pro-resolving mediators (SPMs) can promote tumor progression. Individuals with cystic fibrosis (CF) have a 7–10-fold increased risk of colorectal cancer and a 5–6-fold increased risk of pancreatic cancer. CF carriers have a 2.7-fold increased risk of pancreatic cancer, and a 1.7-fold increased risk of lung cancer compared to non-carriers. To test the hypothesis that abnormalities in lipid metabolites called SPMs play a role in the increased risk of tumor genesis, we took advantage of mice with and without a cystic fibrosis transmembrane conductance regulator defect. Methods: Cystic fibrosis transmembrane conductance regulator exon 10 wild type (WT) and heterozygous mice (HET) (n = 10/group) received subcutaneous injections of Lewis lung carcinoma (LLC) or pancreatic (KPCY) tumor cells. At endpoint, tumors were harvested for lipidomic analysis by gas chromatography–mass spectrometry and liquid chromatography–mass spectrometry. Data were processed with SCIEX Analyst and analyzed in R. Results: In the LLC model, SPMs were significantly lower in HET tumors. 14,15-EET and 8,9-EET were 1,112 and 720 pg/µL in HET vs 2,845 and 1,938 pg/µL in WT, respectively (P = 0.0167 and 0.0210). 4-HDHA was 2,073 pg/µL in HET and 4,279 pg/µL in WT (P = 0.0333). Other SPMs and precursors including 17-HDHA, 14-HDHA, 15-LXA4, RvD3, RvD5, and LXA4 were also lower in HET. Pro-inflammatory mediators such as PGF2α, 9-HODE, and 13-HODE ranged from 1,000–3,000 pg/µL in WT and were consistently lower in HET. For SPMs in KPCY tumors, 8,9-EET was 690 pg/µL in HET and ∼1,500 pg/µL in WT (P = 0.154); 14,15-EET, LXA4, and 15-LXA4 were also lower in HET (P = 0.167, 0.167, 0.381). RvD3 showed no difference (P = 0.694). LLC tumors had higher levels of both pro-resolving and pro-inflammatory mediators than KPCY with genotype effects being more pronounced in LLC. Conclusion: CF heterozygous mice show reduced levels of SPMs and their precursors, including 15-LXA4, RvD3, RvD5, LXA4, 4-HDHA, 17-HDHA, and 14-HDHA, with the greatest reductions observed in lung (LLC) tumors. This loss of resolution, alongside decreased anti-inflammatory EETs (8,9-EET and 14,15-EET) and an imbalance between pro- and anti-inflammatory lipids, can disrupt tumor lipid homeostasis leading to increased cancer risk in CF carriers. These findings provide the first evidence of impaired lipid resolution in CF-associated cancers and identify lipid signaling as a potential therapeutic target.