代谢重编程是癌症的标志，对于癌症进展至关重要，使其成为有吸引力的治疗靶点。了解代谢重编程在癌症发生中的作用有助于确定预防策略。为了解决这个问题，我们研究了腺泡到导管化生（ADM）过程中的代谢，这是胰腺癌发生的第一步。与人类样本的正常组织相比，ADM 病变中的糖酵解标记物升高。使用 Seahorse 测量、核磁共振代谢组分析、质谱、同位素示踪和 RNA 测序分析对三种具有胰腺特异性 KRAS、PI3K 或 MEK1 激活的小鼠模型进行综合代谢评估，揭示了 ADM 中从氧化磷酸化到糖酵解的转变。阻断代谢开关会减弱 ADM 的形成。此外，丝氨酸和谷胱甘肽 (GSH) 的从头合成需要线粒体代谢，但 ATP 的产生不需要线粒体代谢。 MYC 介导 ADM 中 GSH 中间体的增加，抑制 GSH 合成可抑制 ADM 的发展。因此，这项研究确定了胰腺癌发生早期阶段的代谢变化和脆弱性。意义：MYC 介导的从氧化磷酸化到糖酵解的代谢重编程在胰腺癌的发展中发挥着至关重要的作用，揭示了驱动肿瘤发生的机制和潜在的治疗靶点。参见 Storz 的相关评论，第 17 页。 2225.©2024 美国癌症研究协会。

Metabolic reprogramming is a hallmark of cancer and is crucial for cancer progression, making it an attractive therapeutic target. Understanding the role of metabolic reprogramming in cancer initiation could help identify prevention strategies. To address this, we investigated metabolism during acinar-to-ductal metaplasia (ADM), the first step of pancreatic carcinogenesis. Glycolytic markers were elevated in ADM lesions compared with normal tissue from human samples. Comprehensive metabolic assessment in three mouse models with pancreas-specific activation of KRAS, PI3K, or MEK1 using Seahorse measurements, nuclear magnetic resonance metabolome analysis, mass spectrometry, isotope tracing, and RNA sequencing analysis revealed a switch from oxidative phosphorylation to glycolysis in ADM. Blocking the metabolic switch attenuated ADM formation. Furthermore, mitochondrial metabolism was required for de novo synthesis of serine and glutathione (GSH) but not for ATP production. MYC mediated the increase in GSH intermediates in ADM, and inhibition of GSH synthesis suppressed ADM development. This study thus identifies metabolic changes and vulnerabilities in the early stages of pancreatic carcinogenesis. Significance: Metabolic reprogramming from oxidative phosphorylation to glycolysis mediated by MYC plays a crucial role in the development of pancreatic cancer, revealing a mechanism driving tumorigenesis and potential therapeutic targets. See related commentary by Storz, p. 2225.©2024 American Association for Cancer Research.