Vélez-Bonet Ericka, Gumpper-Fedus Kristyn, Chasser Kaylin, Hurst Zachary, Hsueh Hsiang-Yin, Pita-Grisanti Valentina, Liette Alexus, Vulic Grace, Choueiry Fouad, Zhang Huan, Zhu Jiangjiang, Knoblaugh Sue E, Culp Stacey, Volek Jeff S, Cruz-Monserrate Zobeida
Department of Internal Medicine, Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH.
The Comprehensive Cancer Center, The Ohio State University, Columbus, OH.
bioRxiv. 2025 May 24:2025.05.20.655200. doi: 10.1101/2025.05.20.655200.
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). We hypothesized that ketone bodies and a KD alter cell and tumor metabolism. 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. These findings suggest potential benefits of a KD in preventing obesity-associated PDAC, but highlights some risks in non-obese settings.
胰腺导管腺癌（PDAC）是一种侵袭性癌症，预后较差。肥胖是包括PDAC在内的多种癌症的危险因素，这是由于代谢失调和炎症所致。生酮饮食（KD）可改变新陈代谢，并且已使用基因工程小鼠模型（GEMMs）评估了其对非肥胖而非肥胖PDAC肿瘤进展的影响。我们假设酮体和KD会改变细胞和肿瘤的新陈代谢。我们发现酮处理改变了PDAC细胞中的嘧啶代谢。此外，在肥胖的PDAC GEMM中，KD可独立于体重减轻而阻止肿瘤进展，但在非肥胖的PDAC GEMM中会促进PDAC。KD对肥胖相关PDAC的特异性延迟与嘧啶、半胱氨酸和蛋氨酸以及精氨酸和脯氨酸途径中的胰腺代谢变化有关。这些发现表明KD在预防肥胖相关PDAC方面具有潜在益处，但也凸显了在非肥胖情况下的一些风险。
