Prolonged high fat dietary intake increases pancreatic intraepithelial neoplasia to cancer progression

Background: Emerging evidence implicates dietary macronutrient composition as a key modulator of pancreatic tumorigenesis. While the high-fat diet (HFD) drives acinar-to-ductal metaplasia (ADM) and pancreatic intraepithelial neoplasia (PanIN) progression in Kras G12D mice, the impact of ketogenic diet (KD) remains controversial. To determine how KD affects early Kras -driven neoplasia, we investigated the effects of KD, HFD, and low-fat diet (LFD) on pancreatic disease initiation and progression using the Ptf1a CreERT2 Kras G12V (KC Acinar ) mouse model. Methods : Six- to eight-week-old KC Acinar and wild-type (WT) mice were maintained on standard chow (SD) or switched to LFD, HFD, or KD for four weeks before tamoxifen-induced Kras G12V activation. Mice were monitored for survival, body weight, and glucose tolerance. Pancreatic tissues were collected for histopathological evaluation, trichrome staining, and immunohistochemistry. Reverse-phase protein array (RPPA) of pancreatic lysates and serum cytokine profiling were performed to assess signaling and systemic changes. Results: KD-fed KC Acinar 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 also reduced survival compared with SD (35 ± 25; p = 0.05). KD feeding induced glucose intolerance in both WT and KC Acinar mice. Histological analysis revealed that both KD- and HFD-fed KC Acinar mice developed a higher incidence of invasive PDAC with fibrosis, accompanied by reduced CD8⁺ T-cell infiltration and increased stromal CD39 expression relative to tumor compartments. Proteomic profiling showed increased Akt, phospho-S6, Paxillin, and YTHDF2, and decreased PUMA, STAT5A, PHGDH, FASN, and ASNS expression in KD- and HFD-fed KC Acinar mice. Pathway enrichment analysis identified upregulation of EGFR tyrosine kinase inhibitor resistance, chemokine, PI3K-Akt-mTOR, Rap1, and VEGF signaling pathways. Serum cytokine profiling further revealed elevated systemic levels of Ang-2, CCL6, LDLR MMP-9, PAI-1, PTX3, TNFSF13B, and OPG in KD-fed KC Acinar mice. Conclusions: Dietary lipid content before oncogenic Kras activation critically shapes pancreatic cancer development. Both ketogenic and high-fat diets accelerated progression from PanIN to invasive PDAC, accompanied by fibrosis, immune suppression, and activation of PI3K-Akt-mTOR and EGFR signaling. These findings reveal that lipid-rich diets can potentiate oncogenic and inflammatory pathways in the pancreas and caution against the use of ketogenic diets in prevention settings or early stages of pancreatic cancer.