Dysfunctional circadian clock accelerates cancer metastasis by intestinal microbiota triggering accumulation of myeloid-derived suppressor cells

IF 27.7 1区生物学 Q1 CELL BIOLOGY

Cell metabolism Pub Date : 2024-06-04 DOI:10.1016/j.cmet.2024.04.019

Jing-Lin Liu, Xu Xu, Youlutuziayi Rixiati, Chu-Yi Wang, Heng-Li Ni, Wen-Shu Chen, Hui-Min Gong, Zi-Long Zhang, Shi Li, Tong Shen, Jian-Ming Li

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Abstract

Circadian homeostasis in mammals is a key intrinsic mechanism for responding to the external environment. However, the interplay between circadian rhythms and the tumor microenvironment (TME) and its influence on metastasis are still unclear. Here, in patients with colorectal cancer (CRC), disturbances of circadian rhythm and the accumulation of monocytes and granulocytes were closely related to metastasis. Moreover, dysregulation of circadian rhythm promoted lung metastasis of CRC by inducing the accumulation of myeloid-derived suppressor cells (MDSCs) and dysfunctional CD8⁺ T cells in the lungs of mice. Also, gut microbiota and its derived metabolite taurocholic acid (TCA) contributed to lung metastasis of CRC by triggering the accumulation of MDSCs in mice. Mechanistically, TCA promoted glycolysis of MDSCs epigenetically by enhancing mono-methylation of H3K4 of target genes and inhibited CHIP-mediated ubiquitination of PDL1. Our study links the biological clock with MDSCs in the TME through gut microbiota/metabolites in controlling the metastatic spread of CRC, uncovering a systemic mechanism for cancer metastasis.

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功能失调的昼夜节律通过肠道微生物群引发髓源性抑制细胞的积累加速癌症转移

哺乳动物的昼夜节律平衡是对外界环境做出反应的重要内在机制。然而，昼夜节律与肿瘤微环境（TME）之间的相互作用及其对转移的影响仍不清楚。在本研究中，结直肠癌（CRC）患者的昼夜节律紊乱以及单核细胞和粒细胞的聚集与转移密切相关。此外，昼夜节律失调通过诱导小鼠肺部髓源性抑制细胞（MDSCs）和功能失调的CD8+ T细胞聚集，促进了CRC的肺转移。此外，肠道微生物群及其衍生代谢产物牛磺胆酸（TCA）通过引发小鼠肺部MDSCs的聚集，促进了CRC的肺转移。从机制上讲，TCA通过增强靶基因H3K4的单甲基化和抑制CHIP介导的PDL1泛素化，从表观遗传学上促进了MDSCs的糖酵解。我们的研究通过肠道微生物群/代谢物将生物钟与TME中的MDSCs联系起来，控制了CRC的转移扩散，揭示了癌症转移的系统机制。

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来源期刊

Cell metabolism 生物-内分泌学与代谢

CiteScore

48.60

自引率

1.40%

发文量

173

审稿时长

2.5 months

期刊介绍： Cell Metabolism is a top research journal established in 2005 that focuses on publishing original and impactful papers in the field of metabolic research.It covers a wide range of topics including diabetes, obesity, cardiovascular biology, aging and stress responses, circadian biology, and many others. Cell Metabolism aims to contribute to the advancement of metabolic research by providing a platform for the publication and dissemination of high-quality research and thought-provoking articles.