Dietary Fat Content Influences PanIN Progression and Pancreatic Cancer Development in Mice

Dietary macronutrient composition has emerged as a key modulator of pancreatic tumorigenesis, yet the impact of lipid-rich diets, particularly ketogenic diets (KD), on the earliest stages of pancreatic cancer development remains unclear. To investigate how dietary lipids shape the initiation and progression of Kras-driven neoplasia, we examined the effects of a low-fat diet (LFD), high-fat diet (HFD), and KD in the Ptf1a^CreERT2;Kras^G12V (Acinar^KrasG12V) mouse model. KD-fed mice showed the shortest survival (median 26 ± 7 days) compared with the standard diet (SD, 87 ± 29; P = 0.02) and LFD (57 ± 27; P = 0.02), whereas HFD-fed mice also exhibited reduced survival relative to SD (35 ± 25; P ¼ 0.05). KD feeding was associated with severe glucose intolerance and elevated circulating β-hydroxybutyrate levels. Histologically, KD-fed Acinar^KrasG12V mice developed invasive, sarcomatoid-like pancreatic ductal adenocarcinoma (PDAC), whereas HFD-fed mice showed increased poorly differentiated PDAC; in both groups, these aggressive tumors were associated with extensive fibrosis and increased stromal CD39 expression relative to tumor compartments. Proteomic analysis demonstrated activation of the PI3K–Akt–mTOR and EGFR signaling pathways in tumors from KD- and HFD-fed Acinar^KrasG12V mice. Serum cytokine/chemokine profiling revealed a proinflammatory and proangiogenic milieu in KD-fed Acinar^KrasG12V mice. Collectively, these results suggest that dietary lipid enrichment prior to oncogenic Kras activation is associated with accelerated early pancreatic neoplasia and a microenvironment conducive to tumor progression. These findings underscore the need for careful consideration of KD use in individuals at elevated risk for pancreatic cancer. Significance: This article evaluates the impact of KDs and HFDs prior to oncogenic Kras activation in the Acinar^KrasG12V model. These findings reveal that lipid-rich diets accelerate PDAC progression and have important implications for dietary recommendations in individuals at elevated pancreatic cancer risk.