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Masri S
; Papagiannakopoulos T
; Kinouchi K
; Liu Y
; Cervantes M
; Baldi P
; Jacks T
; Sassone-Corsi P
Cell
2016[May]; 165
(4
): 896-909
PMID27153497
show ga
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.
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