Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis.
Lung Adenocarcinoma Distally Rewires Hepatic Circadian Homeostasis.
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DOI：
10.1016/j.cell.2016.04.039
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发表时间：
2016-05-05
期刊：
影响因子：
64.5
通讯作者：
Sassone-Corsi P
中科院分区：
文献类型：
--
作者：
Masri S;Papagiannakopoulos T;Kinouchi K;Liu Y;Cervantes M;Baldi P;Jacks T;Sassone-Corsi P
生物钟通过精细调节的分子机制控制代谢和生理过程。生物钟具有显著的可塑性，能够适应外部的授时因子，比如光线和营养。特定组织中的病理状况如何影响其他组织的系统昼夜节律稳态仍然是一个未解决的概念和生物医学重要性问题。在这里，我们表明肺腺癌作为一种内源性的昼夜代谢重组者运作。高通量转录组学和代谢组学揭示了肿瘤小鼠肝脏中转录物和代谢物循环的独特特征。值得注意的是，肺癌对核心时钟没有影响，而是通过STAT3-Socs3通路改变促炎反应，重编程肝脏代谢。这导致AKT、AMPK和SREBP信号的破坏，导致胰岛素、葡萄糖和脂质代谢的改变。因此，肺腺癌作为一种强有力的内源性昼夜节律组织者（ECO）发挥作用，它重新连接了远端组织（如肝脏）的病理生理维度。
The circadian clock controls metabolic and physiological processes through finely tuned molecular mechanisms. The clock is remarkably plastic and adapts to exogenous zeitgebers, such as light and nutrition. How a pathological condition in a given tissue influences systemic circadian homeostasis in other tissues remains an unanswered question of conceptual and biomedical importance. Here we show that lung adenocarcinoma operates as an endogenous reorganizer of circadian metabolism. High-throughput transcriptomics and metabolomics revealed unique signatures of transcripts and metabolites cycling exclusively in livers of tumor-bearing mice. Remarkably, lung cancer has no effect on the core clock, but rather reprograms hepatic metabolism through altered pro-inflammatory response via the STAT3-Socs3 pathway. This results in disruption of AKT, AMPK and SREBP signaling, leading to altered insulin, glucose and lipid metabolism. Thus, lung adenocarcinoma functions as a potent endogenous circadian organizer (ECO), which rewires the pathophysiological dimension of a distal tissue such as the liver.