Department of Pathology, Sun Yat-sen Memorial Hospital, Sun Yat-sen University, Guangzhou 510120, China.
Department of Pathology, Soochow Medical College, Soochow University, Suzhou 215123, China.
Cell Metab. 2024 Jun 4;36(6):1320-1334.e9. doi: 10.1016/j.cmet.2024.04.019.
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.
哺乳动物的昼夜节律内稳态是应对外部环境的关键内在机制。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。在这里，在结直肠癌（CRC）患者中，昼夜节律紊乱和单核细胞和粒细胞的积累与转移密切相关。此外，昼夜节律失调通过诱导小鼠肺部髓系来源抑制细胞（MDSC）和功能失调的 CD8 T 细胞的积累，促进 CRC 的肺转移。同样，肠道微生物群及其衍生代谢物胆酸（TCA）通过触发小鼠 MDSC 的积累，导致 CRC 的肺转移。在机制上，TCA 通过增强靶基因 H3K4 的单甲基化，促进 MDSC 的糖酵解，并抑制 CHIP 介导的 PDL1 泛素化。我们的研究通过肠道微生物群/代谢物将生物钟与 TME 中的 MDSC 联系起来，从而控制 CRC 的转移扩散，揭示了癌症转移的系统机制。
