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 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 SD (87 ± 29; p = 0.02) and LFD (57 ± 27; p = 0.02), while HFD-fed mice also exhibited reduced survival relative to SD (35 ± 25; p = 0.05). KD feeding induced severe glucose intolerance and elevated circulating β-hydroxybutyrate levels. Histologically, KD-fed Acinar ^KrasG12V mice developed invasive, sarcomatoid-like pancreatic ductal adenocarcinoma (PDAC), while 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 PI3K-Akt-mTOR and EGFR signaling in KD and HFD-fed Acinar ^KrasG12V mice. Serum cytokines/chemokines profiling revealed pro-inflammatory and pro-angiogenic milieu in KD-fed Acinar ^KrasG12V mice. Collectively, these results show that dietary lipid enrichment prior to oncogenic Kras activation may accelerate early pancreatic neoplasia and foster 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.