Abstract Background: Pancreatic ductal adenocarcinoma (PDAC) is an aggressive cancer with poor outcomes. Obesity is a risk factor for several cancers including PDAC due to metabolic dysregulation and inflammation. The ketogenic diet (KD) can alter metabolism and has been evaluated for its effects on tumor progression in non-obese but not obese PDAC using genetically engineered mouse models (GEMMs). Purpose: To examine ketone treatment on PDAC metabolism and KD effects on tumor development in obesity-associated and non-obese PDAC. We examined tumor-specific metabolomic differences associated with dietary modifications after obesity-associated PDAC. Methods: PDAC cells were treated with sodium 3-hydroxybutyrate or lithium acetoacetate, followed by untargeted metabolomic analysis. PDAC GEMMs were subjected to either diet-induced obesity (DIO) using a 45% high-fat diet (HFD), as it mimics a more physiologically relevant DIO in humans, a DIO higher in fat content (60% HFD) or a low-fat (non-obese) diet for 15 weeks. Mice were then randomized to remain on their respective diets or switched to a KD or a KD control (KDC) diet for a 6-week intervention. Body composition was measured using an EchoMRI. Body weight, glucose tolerance, and ketone levels were measured at different timepoints. Tumors metabolomics were analyzed by Liquid Chromatography Mass Spectrometry (LC-MS). Results: We show that ketone treatments altered pyrimidine metabolism in PDAC cells. Moreover, in an obese PDAC GEMM, KD prevented tumor progression independent of weight loss but promoted PDAC in a non-obese PDAC GEMM. The KD-specific delay of obesity-associated PDAC was associated with pancreatic metabolic shifts in pyrimidine, cysteine and methionine, and arginine and proline pathways. Conclusions: These findings suggest potential benefits of a KD in preventing obesity-associated PDAC but highlights some risks in non-obese settings. The associated tumor-specific metabolic alterations point to nutrient pathways that may contribute to KD mediated tumor suppression in obesity and represent targets for future intervention. Citation Format: Ericka Velez-Bonet, Kristyn Gumpper-Fedus, Kaylin Chasser, Zachary Hurst, Hsiang-Yin Hsueh, Valentina Pita-Grisanti, Alexus Liette, Grace Vulic, Fouad Choueiry, Huan Zhang, Jiangjiang Zhu, Sue E. Knoblaugh, Stacey Culp, Jeff S. Volek, Zobeida Cruz-Monserrate. Ketogenic diet prevents obesity-associated pancreatic cancer independent of weight loss and induces pancreatic metabolic reprogramming abstract. In: Proceedings of the AACR Special Conference in Cancer Research: Advances in Pancreatic Cancer Research—Emerging Science Driving Transformative Solutions; Boston, MA; 2025 Sep 28-Oct 1; Boston, MA. Philadelphia (PA): AACR; Cancer Res 2025;85 (18Suppl₃): Abstract nr A034.
Vélez-Bonet et al. (Sun,) studied this question.