Tumor Macroenvironment and the Circadian Metabolic Clock

项目摘要/摘要 癌细胞表现出更高的代谢需求，这是由增加的 有氧糖酵解的速度，称为沃堡效应。然而，这种新陈代谢的需求 癌细胞还会产生代谢的“废物”副产物，这些副产物会被全身分泌。 例如，糖酵解的副产物乳酸据报道与新陈代谢有关。 对邻近组织重新编程，并可诱导促炎反应。 同样，据报道，肿瘤来源的促炎细胞因子也会改变 代谢组织的功能，如肝脏、脂肪和胰腺。我们假设 这些肿瘤相关的代谢废物和炎性细胞因子， 所谓的肿瘤‘大环境’可以远端重新编程昼夜节律的功能 肝脏和胰腺的新陈代谢时钟。使用肺腺癌小鼠模型， 我们假设肿瘤大环境抑制时钟控制的胰岛素 肺肿瘤(TB)小鼠的分泌物，导致肝脏的比率增加 糖异生作用。我们的目标是为生物钟的变化提供分子机制- 控制肝脏葡萄糖的产生。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，并且 将进行实验来解决这一问题。我们还假设 炎症反应以胰岛功能为靶点，随后导致 抑制胰岛素的产生或分泌。我们提出了一种新陈代谢图谱 以无偏倚的方式确定哪种肿瘤- 依赖的代谢物可能介导这种与外周代谢的串扰 钟表，如肝脏和胰腺。总体而言，我们假设肿瘤 宏观环境可能在重新规划昼夜新陈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 潜在的治疗癌症的系统治疗新策略。

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.