Understanding omega-3 and 6 fatty acid dependent regulation of inflammatory signals in pancreatic cancer

PROJECT SUMMARY Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer with a five-year survival rate of just over 10%. Its incidence is rising and is projected to become the second leading cause of cancer deaths by 2030, with obesity increasing risk by 20-50%. Obesity induces chronic inflammation, and inflammation has been found to be essential in driving PDAC, as KRAS mutations alone cannot initiate tumorigenesis without an inflammatory trigger. Normally, inflammation aids wound healing by stimulating the next phase of tissue regeneration, but unresolved chronic inflammation leads to sustained cell proliferation and fibrosis, which drives cancer progression. Understanding how to resolve inflammation and restore tissue homeostasis is key to preventing chronic inflammation and progression to PDAC. A hallmark of wound resolution is lipid-mediator class-switching, where cells shift from producing pro- inflammatory signaling lipids to those promoting resolution. These bioactive lipids arise from omega-3 (n-3) and omega-6 (n-6) polyunsaturated fatty acids (PUFAs). Typical n-6 PUFAs such as linoleic acid (LA) and arachidonic acid (AA) are metabolized into pro-inflammatory mediators like leukotrienes and prostaglandins. Typical n-3 PUFAs, such as eicosapentaenoic acid (EPA) and docosahexaenoic acid (DHA), are converted into anti-inflammatory specialized pro-resolution mediators (SPMs) like resolvins, protectins, and maresins. Both ‘upstream’ n-3 PUFA signaling and ‘downstream’ SPM signaling suppress inflammation and aid healing. Dietary fish oil, rich in n-3 PUFAs, is linked to reduced pancreatic tumorigenesis, though mechanisms remain unclear. Our preliminary data support the central hypothesis that dietary n-3 PUFAs promote lipid class-switching, reduce inflammation and slow PDAC progression, but the pathways involved require further investigation. Comparisons of the PDAC tumor microenvironment (TME) between mice fed n-6 and n-3 high fat diets (HFDs) show that many inflammatory cytokines and IL-6 family members decrease, while 18-HEPE and 17-HDoHE, resolvin precursors, accumulate in tumors from n-3 fed mice. Tumor-associated macrophages (TAMs) mediate this lipid switching, with n-3 PUFAs enhancing MHC-II and Cxcl16 expression while reducing Il6, Lif, and Arginase1 levels. This suggests that n-3 PUFA metabolism reshapes TAM function and metabolism to suppress tumor growth. To clarify the underlying mechanisms of action of n-3 PUFAs in PDAC, we will examine: 1) which cells drive tumor repression by n-3 PUFA production, 2) how signaling through GPR120 and SPMs suppress PDAC, 3) how shifts in macrophage states limit PDAC by inhibiting IL-6-family members or increasing MHC-II- CD4 T cell interactions, and 4) how n-3 PUFAs affect epigenetic remodeling and ‘inflammatory memory’ in macrophages, fibroblasts, and tumor cells. This study will uncover key signaling, metabolic, and epigenetic mechanisms by which dietary lipids reduce inflammation and prevent cancer.