Department of Clinical Medicine-Clinical Department for Internal Medicine II, TUM School of Medicine and Health, University Medical Center, Technical University of Munich, Munich, Germany.
Technical University of Munich, TUM School of Medicine and Health, Institute of Pathology, Comparative Experimental Pathology, Munich, Germany.
Cancer Res. 2024 Jul 15;84(14):2297-2312. doi: 10.1158/0008-5472.CAN-23-2213.
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.
代谢重编程是癌症的一个标志，对癌症的进展至关重要，使其成为一个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可能有助于确定预防策略。为了解决这个问题，我们研究了在胰腺发生的第一步——腺泡到导管的化生（ADM）过程中的代谢。与来自人类样本的正常组织相比，ADM 病变中的糖酵解标志物升高。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，在三种具有胰腺特异性 KRAS、PI3K 或 MEK1 激活的小鼠模型中进行全面的代谢评估，揭示了 ADM 中从氧化磷酸化到糖酵解的转变。阻断代谢转换可减弱 ADM 的形成。此外，线粒体代谢对于丝氨酸和谷胱甘肽（GSH）的从头合成是必需的，但对于 ATP 产生不是必需的。MYC 介导了 ADM 中 GSH 中间产物的增加，而 GSH 合成的抑制则抑制了 ADM 的发展。因此，本研究确定了胰腺癌发生早期的代谢变化和脆弱性。意义：由 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起着至关重要的作用，揭示了驱动肿瘤发生的机制和潜在的治疗靶点。见相关评论，第 2225 页。
