UC Davis

A significant number of pancreatic cancer cases are due to modifiable risk factors, with many being attributed to increased body fatness. This has sparked investigators to examine the role played by high dietary fat intake in pancreatic cancer development and the mechanisms driving this connection. However, there is currently no consensus on how dietary fat quantity and composition specifically affect the tumor microenvironment and pancreatic cancer incidence.The introduction provides a thorough review of the current literature regarding the effect of dietary fat quantity and composition on pancreatic carcinogenesis in preclinical and epidemiological research studies. We summarize current advances and controversies within the field and highlight important research gaps to be addressed in future studies. The mechanisms of obesity in pancreatic carcinogenesis are complex, including the secretion of growth factors, signaling pathway perturbations, hormones, and inflammatory molecules. We conclude that given the current preclinical evidence, diets high in omega-3 fatty acids (FA) appear to be associated with reduced pancreatic cancer risk, while omega-6 FA appear to enhance pancreatic cancer development. Moreover, the current research surrounding the effect of diets high in saturated fats and monounsaturated fats appears to be inconclusive and warrants further research. Given these gaps in knowledge, my thesis objective was to investigate how dietary fat quantity and composition specifically affect the tumor microenvironment and pancreatic cancer incidence. The aim of chapter 1 was to evaluate the effect of dietary fat quantity on changes in mesenteric adipose tissue (MAT) and the impact on pancreatic carcinogenesis in a clinically relevant KrasLSL-G12D/+; Ptf1aCre/+ (KC) mouse model of pancreatic cancer. KC mice were fed a control diet (CD- 10% kcal from fat and a 10:1 of omega-6 FA: omega-3 FA) or a high-fat diet (HFD- 60% kcal from fat and a 10:1 ratio of omega-6 FA: omega-3 FA) for eight weeks. I observed that KC mice fed a HFD had significantly higher body weight, fat mass, and serum leptin compared to CD-fed KC mice. Furthermore, HFD-fed mice had significantly higher acinar-to-ductal metaplasia (ADM), cell proliferation, and phosphorylation of ERK and STAT3 levels compared to CD-fed KC mice. Feeding a HFD also affected many parameters at the MAT. I observed a significant increase in linoleic acid in MAT of HFD-fed KC mice, which may act as a source of lipids for metaplastic cells of the pancreas. Additionally, I observed sex dependent differences in MAT metabolites between diet groups. On a HFD, females displayed significant reductions in aspartate and glutamate, while in males, there was a significant increase in aspartate and glutamate found in MAT. These differences in metabolites between sexes might explain why males are at a high risk of developing pancreatic cancer compared to females, although additional studies are warranted to further assess this hypothesis. The overall goal of chapter 2 was to assess the impact of dietary fat composition on changes in MAT and its impact on pancreatic carcinogenesis in a KC mouse model of pancreatic cancer. The first sub-aim was to assess the impact of omega-3 FA, in the context of obesity, on changes to surrounding adipose tissue and pancreatic cancer incidence. KC mice were allocated to either a high-fat diet (HF- 60% kcal from fat and 9:1 of omega-6 FA: omega-3 FA) or a high-fat, high omega-3 diet (HO- 60% kcal from fat and a 1:1 of omega-6 FA: omega-3 FA) for eight weeks. After 8 weeks, the HO-fed KC mice displayed significantly lower body weight gain, fat mass, serum leptin and IL-6. The HO-fed KC mice additionally demonstrated improvements in liver triglyceride deposition compared to the HF-fed KC mice. I observed a significant reduction in ADM paired with a decrease in metaplastic mucinous epithelial cells, cell proliferation, and phosphorylation of key pathway STAT3 at the pancreas level. At the MAT level, the HO diet resulted in reduced MAT weight, adipocyte size and an increase in anti-inflammatory M2 macrophages compared to HF-fed KC mice. Overall, the results in the first sub-aim demonstrate that females might benefit more from omega-3 FA consumption than males, in the context of pancreatic carcinogenesis. The second sub-aim of chapter 2 was to assess the impact of a dietary switch, after the induction of obesity, to a diet high in omega-3 FA on surrounding adipose tissue and pancreatic cancer incidence. KC mice were allocated to either a HF diet group (60% kcal from fat and 9:1 of omega-6 FA: omega-3 FA) for 21 weeks or a HFHO diet group that consumed the HF diet for eight weeks until 3 months of age, followed by a dietary switch to the HO diet for 13 weeks until 6 months of age (60% kcal from fat and a 1:1 of omega-6 FA: omega-3 FA). HFHO-fed KC mice demonstrated reductions in body weight gain and fat mass after 21 weeks on diet. Additionally, I observed significant increases in serum adiponectin, associated with improved energy metabolism and IFN-γ, associated with elevated immune activation. At the pancreas level, we observed significant reductions in metaplastic mucinous epithelial cells and collagen deposition in HFHO- fed KC mice. At the MAT level, I noted differences only in reduced MAT weight and adipocyte size with no effect on the infiltration or polarization of macrophages in HFHO-fed KC mice. Furthermore, significant metabolite differences of peripancreatic adipose tissue (PPAT) were identified in female KC mice with no differences found in male KC mice. Female HFHO-fed KC mice demonstrated increases in several mono-unsaturated FA, including docosenoic acid and pentadecanoic acid, that have been previously shown to attenuate inflammation. In summary, results from my thesis suggest that dietary fat quantity appears to be a more important predictor of pancreatic cancer risk compared to the dietary fat composition. Our findings indicate that high-fat diets are promoters of early stage pancreatic carcinogenesis by enhancing ADM, cell proliferation and polarization of infiltrating immune cells, with a marked increase in pro-inflammatory metabolites found in surrounding adipose tissue depots in close proximity to cancer cell. On the other hand, omega-3 FA appear to be able to partially mitigate these effects induced by a HFD prior to the induction of obesity. In addition, a dietary switch to a diet high in omega-3 FA is not fully able to mitigate the effects of obesity and HFD consumption. Finally, females could benefit more from omega-3 FA consumption in reducing adipose tissue inflammation.