Human metabolic variation as a window into cancer initiation and progression

人类代谢变异是了解癌症发生和进展的窗口

基本信息

批准号：
10736053
负责人：
RALPH J DEBERARDINIS
金额：
$ 96.7万
依托单位：
UT SOUTHWESTERN MEDICAL CENTER
依托单位国家：
美国
项目类别：
财政年份：
2017
资助国家：
美国
起止时间：
2017-09-04 至 2030-08-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10736053
关键词：
Advanced Malignant Neoplasm Biochemical Pathway Biopsy Cancer Model Cancer Patient Cells Cessation of life Citric Acid Cycle Clear cell renal cell carcinoma Clinical Data Defect Dependence Electron Transport Excision Glucose Human Inborn Errors of Metabolism Infusion procedures Isotope Labeling Isotopes Kidney Label Malignant - descriptor Malignant Neoplasms Measures Metabolic Methodology Methods Mus Neoplasm Metastasis Non-Small-Cell Lung Carcinoma Nutrient Oxidative Phosphorylation Pathway interactions Patient-Focused Outcomes Patients Physiological Procedures Productivity Property Sampling Series Site Source Stable Isotope Labeling Techniques Time Tracer Variant Work cancer initiation cohort experimental study imaging modality insight metabolic abnormality assessment mitochondrial metabolism mouse model novel therapeutics rare genetic disorder success therapeutic target therapy resistant tumor tumor metabolism tumor progression

项目摘要

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.

项目摘要/摘要代谢重编程是恶性肿瘤的标志，也是治疗靶标的潜在来源。最近的工作表明代谢负债随着癌症的进展而发生变化，这意味着与在原产地，晚期癌症可能并不明显。认识到有关人类癌症代谢的直接信息的死亡，我们开发了一种方法通过注入稳定的同位素标记的营养素来探测完整人肿瘤的代谢网络（例如13C-葡萄糖）在肿瘤切除或活检过程中。通过测量从从中提取的代谢物中的同位素标记肿瘤样本并遵循接受此过程的患者的结果，我们确定了代谢与存活不良有关的特性。数百种代谢特征，三核酸中的13C标记（TCA）循环代谢产物是癌症进展和早期死亡的最终预测。在非小细胞肺中癌症（NSCLC），这些代谢产物的肿瘤标记很高的患者比标记低的患者，在NSCLC小鼠模型中阻止这种途径可抑制转移。在清晰的细胞肾细胞癌（CCRCC），当肿瘤局部放在肾脏中时，TCA周期标签很低，但转移性肿瘤中的更高，激活TCA循环会促进小鼠的转移。因此，在这两个方面癌症的种类，来自患者的数据导致我们包括氧化性线粒体代谢，尤其是 TCA循环，电子传输链（ETC）和氧化磷酸化（OXPHOS）促进癌症的进展。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开发新的见解和疗法。我们提出了三个一般方向。首先，使用一个人类和小鼠的方法的结合，我们将彻底研究线粒体代谢如何刺激转移以识别可以安全针对患者的离散代谢依赖性。其次，我们将开发发现人类肿瘤中新代谢责任的方法。策略包括在生理条件下，探测具有一系列同位素标记营养素的探测可行肿瘤外植体的管道选择患者的同位素输注最有用的示踪剂；和动态成像方法观察并实时量化肿瘤中代谢通量的信息。第三，我们将使用正交研究人类天生代谢错误（IEM）的方法，以发现为什么某些代谢异常主要细胞变得恶性。这种方法大写了1,000多名受试者的临床人群，包括与高渗透癌相关的IEM患者，将为癌症开始提供独特的见解和进展。这些努力将基于我们在人类癌症代谢中长期生产力的基础通过发现管理癌症进展代谢基础并产生新机制理解和治疗致命恶性肿瘤的方法。

项目成果

期刊论文数量（34）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Lkb1 deficiency confers glutamine dependency in polycystic kidney disease.

DOI：
10.1038/s41467-018-03036-y
发表时间：
2018-02-26
期刊：
Nature communications
影响因子：
16.6
作者：
Flowers EM;Sudderth J;Zacharias L;Mernaugh G;Zent R;DeBerardinis RJ;Carroll TJ
通讯作者：
Carroll TJ

p53 deficiency triggers dysregulation of diverse cellular processes in physiological oxygen.

DOI：
10.1083/jcb.201908212
发表时间：
2020-11-02
期刊：
The Journal of cell biology
影响因子：
0
作者：
Valente LJ;Tarangelo A;Li AM;Naciri M;Raj N;Boutelle AM;Li Y;Mello SS;Bieging-Rolett K;DeBerardinis RJ;Ye J;Dixon SJ;Attardi LD
通讯作者：
Attardi LD

Lactate metabolism is essential in early-onset mitochondrial myopathy.