Human metabolic variation as a window into cancer initiation and progression

项目总结/摘要 代谢重编程是恶性肿瘤的标志和治疗靶点的潜在来源。最近的工作 表明代谢负债随着癌症的进展而变化，这意味着与癌症最相关的途径 晚期癌症在起源部位的局部侵袭性、未经治疗的肿瘤中可能不明显。 认识到缺乏有关人类癌症代谢的直接信息，我们开发了一种方法， 通过向患者输注稳定的同位素标记的营养物质来探测完整人类肿瘤的代谢网络 (e.g. 13 C-葡萄糖）。通过测量从植物中提取的代谢物中的同位素标记， 肿瘤样本，并遵循接受此程序的患者的结果，我们确定了代谢 与生存不良相关的属性。在数百种代谢特征中，三羧酸中的13 C标记 (TCA)周期代谢物是癌症进展和早期死亡的最佳预测因子。非小细胞肺癌 在非小细胞肺癌（NSCLC）中，其肿瘤具有这些代谢物的高标记的患者比其他患者早得多地死亡。 在NSCLC小鼠模型中阻断这一途径可抑制转移。在 透明细胞肾细胞癌（ccRCC），当肿瘤位于肾脏时，TCA循环标记较低， 在转移性肿瘤中高得多，并且激活TCA循环促进小鼠的转移。因此，在两者中 从患者的数据中，我们得出结论，氧化线粒体代谢，特别是 TCA循环、电子传递链（ETC）和氧化磷酸化（OxPhos）促进癌症进展。 这些实验的成功促使我们进一步研究人类癌症进展的代谢基础 希望能发展出新的见解和疗法我们提出三个大方向。首先，使用 结合人类和小鼠的方法，我们将彻底研究线粒体代谢如何 刺激转移，以确定可以安全靶向患者的离散代谢依赖性。 其次，我们将开发方法来发现人类肿瘤中新的代谢负债。战略包括 在生理条件下用一系列同位素标记的营养物探测存活肿瘤外植体的管道 选择最具信息量的示踪剂用于患者的同位素输注;动态成像方法用于观察 并在真实的时间内量化肿瘤中代谢流的信息方面。第三，我们将使用正交 研究人类先天性代谢缺陷（IEMS）的方法，以发现为什么某些代谢异常 导致细胞恶性化该方法利用了超过1，000名受试者的临床队列，包括 与高度渗透性癌症相关的IEM患者，并将为癌症的发生提供独特的见解 和进步。总之，这些努力将建立在我们长期以来在人类癌症代谢方面的生产力基础上 通过揭示控制癌症进展代谢基础的新机制， 了解和治疗致命恶性肿瘤的方法。

PROJECT SUMMARY/ABSTRACT Metabolic reprogramming is a hallmark of malignancy and potential source of therapeutic targets. Recent work indicates that metabolic liabilities change as cancer progresses, meaning that the pathways most relevant to advanced cancers may not be apparent in locally-invasive, treatment-naïve tumors at the site of origin. Recognizing the dearth of direct information about human cancer metabolism, we developed an approach to probe the metabolic network of intact human tumors by infusing patients with stable isotope-labeled nutrients (e.g. 13C-glucose) during tumor resection or biopsy. By measuring isotope labeling in metabolites extracted from tumor samples and following the outcomes of patients who underwent this procedure, we identified metabolic properties associated with poor survival. Of hundreds of metabolic features, 13C labeling in tricarboxylic acid (TCA) cycle metabolites was the most predictive of cancer progression and early death. In non-small cell lung cancer (NSCLC), patients whose tumors have high labeling of these metabolites succumb much earlier than patients with low labeling, and blocking this pathway in mouse models of NSCLC suppresses metastasis. In clear cell renal cell carcinoma (ccRCC), TCA cycle labeling is low when tumors are localized to the kidney but much higher in metastatic tumors, and activating the TCA cycle promotes metastasis in mice. Therefore, in both kinds of cancer, data from patients lead us to conclude that oxidative mitochondrial metabolism, particularly the TCA cycle, electron transport chain (ETC) and oxidative phosphorylation (OxPhos), promote cancer progression. The success of these experiments prompts us to further study the metabolic basis of human cancer progression in the hopes of developing new insights and therapies. We propose three general directions. First, using a combination of approaches in humans and mice, we will thoroughly examine how mitochondrial metabolism stimulates metastasis to identify discrete metabolic dependencies that could be safely targeted in patients. Second, we will develop approaches to discover new metabolic liabilities in human tumors. Strategies include a pipeline to probe viable tumor explants with a series of isotope-labeled nutrients under physiological conditions to choose the most informative tracers for isotope infusions in patients; and dynamic imaging methods to observe and quantify informative aspects of metabolic flux in tumors in real time. Third, we will use the orthogonal approach of studying human inborn errors of metabolism (IEMs) to discover why some metabolic anomalies prime cells to become malignant. This approach capitalizes on a clinical cohort of over 1,000 subjects, including patients with IEMs associated with highly penetrant cancers, and will provide unique insights into cancer initiation and progression. Altogether these efforts will build on our long-standing productivity in human cancer metabolism by uncovering new mechanisms governing the metabolic basis of cancer progression and producing new methodologies to understand and treat lethal malignancies.