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

Abstract

UNLABELLED: 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 Ptf1aCreERT2;KrasG12V (AcinarKrasG12V) 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 = 0.05). KD feeding was associated with severe glucose intolerance and elevated circulating β-hydroxybutyrate levels. Histologically, KD-fed AcinarKrasG12V 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 AcinarKrasG12V mice. Serum cytokine/chemokine profiling revealed a proinflammatory and proangiogenic milieu in KD-fed AcinarKrasG12V 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 AcinarKrasG12V 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.