Tumor Macroenvironment and the Circadian Metabolic Clock

肿瘤宏观环境和昼夜代谢钟

• 批准号: 9380530
• 负责人: Selma Masri
• 金额: $ 20.23万
• 依托单位: UNIVERSITY OF CALIFORNIA-IRVINE
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-12-01 至 2020-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9380530
• 关键词: Address; Adenosine Triphosphate; Adipose tissue; Amino Acids; Anti-inflammatory; Cancer Etiology; Carbohydrates; Cell Survival; Cessation of life; Circadian Rhythms; Clinical; Communication; Cues; Data; Distal; Eating; Endocrine; Energy-Generating Resources; Enzymes; Epigenetic Process; Exhibits; Fatty Acids; Fatty acid glycerol esters; Feedback; Gene Expression; Genes; Genetic Transcription; Gluconeogenesis; Glucose; Goals; Hepatic; Inflammation; Inflammatory; Inflammatory Response; Insulin; Islets of Langerhans; Isotope Labeling; Lipids; Lipolysis; Liver; Lung Adenocarcinoma; Lung Neoplasms; Malignant Neoplasms; Malignant neoplasm of lung; Mediating; Metabolic; Metabolism; Metformin; Molecular; Mus; Muscle Mitochondria; Nucleotides; Nutritional; Pancreas; Paracrine Communication; Pathway interactions; Periodicity; Peripheral; Pharmacology; Phenotype; Phosphoenolpyruvate Carboxylase; Physiological; Play; Production; Pyruvate; Reporting; Role; Serum; Therapeutic; Tissues; Tumor-Derived; Warburg Effect; Waste Products; Work; aerobic glycolysis; base; cancer cell; circadian pacemaker; cofactor; cytokine; experimental study; feeding; glucose production; hepatic gluconeogenesis; insulin secretion; lipid biosynthesis; liver function; metabolic profile; metabolomics; mouse model; novel; nutrition; pancreatic islet function; salicylsalicylic acid; transcriptome sequencing; tumor; tumor growth; wasting

Project Summary/Abstract Cancer cells exhibit a heightened metabolic demand that is satisfied by an increased rate of aerobic glycolysis, termed the Warburg effect. Yet, this metabolic demand of cancer cells also results in metabolic ‘waste’ by-products that are secreted systemically. As an example, the glycolytic by-product lactate is reported to be involved in metabolic reprogramming of adjacent tissues and can induce a pro-inflammatory response. Similarly, tumor-derived pro-inflammatory cytokines have been reported to alter functions of metabolic tissues such as liver, fat and the pancreas. We hypothesize that these tumor-dependent metabolic waste by-products and inflammatory cytokines, the so-called tumor ‘macroenvironment,’ can distally reprogram the functions of the circadian metabolic clocks in the liver and pancreas. Using a lung adenocarcinoma mouse model, we hypothesize that the tumor macroenvironment inhibits clock-controlled insulin secretion in lung tumor-bearing (TB) mice, resulting in an enhanced rate of hepatic gluconeogenesis. We aim to provide the molecular mechanism for the changes in clock- controlled hepatic glucose production. Moreover, we propose that this enhanced hepatic glucose production could feedback and satisfy the metabolic demand of the tumor, and experiments will be performed to address this. We also hypothesize that the inflammatory response is targeting pancreatic islet function, subsequently resulting in inhibition of insulin production or secretion. We propose a metabolic profiling of the serum over the circadian cycle to determine in an unbiased manner what tumor- dependent metabolites could be mediating this crosstalk with peripheral metabolic clocks, such as liver and pancreas. Overall, we hypothesize that the tumor macroenvironment could play an important role in reprogramming circadian metabolic functions of the liver and pancreas. This work has important clinical implications for potential novel systemic therapeutic strategies to treat cancer.

项目总结/摘要 癌细胞表现出更高的代谢需求，这是由增加的 有氧糖酵解的速率，称为瓦尔堡效应。然而， 癌细胞还产生全身分泌的代谢“废物”副产物。 作为一个例子，据报道糖酵解副产物乳酸盐参与代谢。 这可能导致邻近组织的重编程，并且可以诱导促炎反应。 类似地，已经报道了肿瘤衍生的促炎细胞因子改变了肿瘤细胞的增殖。 肝脏、脂肪和胰腺等代谢组织的功能。我们假设 这些肿瘤依赖性代谢废物副产物和炎性细胞因子， 所谓的肿瘤“大环境”，可以远端重新编程昼夜节律的功能， 肝脏和胰腺的代谢时钟使用肺腺癌小鼠模型， 我们假设肿瘤大环境抑制了生物钟控制的胰岛素， 在肺肿瘤（TB）小鼠中的分泌，导致肝细胞癌的发生率增加。 异源发生我们的目标是提供生物钟变化的分子机制- 控制肝脏葡萄糖生成。此外，我们认为，这种增强的肝脏 葡萄糖的产生可以反馈和满足肿瘤的代谢需求， 将进行实验来解决这个问题。我们还假设， 炎症反应针对胰岛功能，随后导致 抑制胰岛素的产生或分泌。我们提出了一个代谢谱的 血清在昼夜节律周期，以确定在一个公正的方式什么肿瘤- 依赖性代谢物可能介导这种串扰与外周代谢 时钟，如肝脏和胰腺。总的来说，我们假设肿瘤 大环境可能在重新编程昼夜代谢中发挥重要作用 肝脏和胰腺的功能。这项工作具有重要的临床意义， 治疗癌症的潜在的新的全身性治疗策略。