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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.

项目总结/文摘

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）

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

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

Compartmentalized metabolism supports midgestation mammalian development.