Disruption of Circadian Rhythm Promotes Cancer Metastasis and Myeloid-Derived Suppressor Cell Accumulation Triggered by Intestinal Microbes

Academic Background and Research Motivation

Cancer metastasis is the leading cause of death for most cancer patients, with colorectal cancer (CRC) drawing significant attention due to its high global incidence and mortality rates. Myeloid-derived suppressor cells (MDSCs) are immature myeloid cells derived from hematopoietic stem cells with immunosuppressive activity, primarily promoting tumor immune evasion and invasion by inhibiting T cells, B cells, or natural killer (NK) cell-mediated immune responses. However, the regulatory mechanisms of MDSCs in the tumor microenvironment (TME) remain unclear.

The circadian rhythm is an essential intrinsic mechanism by which organisms adapt to changes in the external environment, maintaining the homeostasis of the internal environment. However, circadian rhythm disorders are closely associated with various diseases, particularly cancer, where tumor cells are more likely to accelerate their progression during sleep. This study aims to explore how circadian rhythm disruption, through intestinal microbes and their metabolites, promotes CRC metastasis and the accumulation of MDSCs.

Research Source and Author Information

This paper was published in the June 4, 2024 issue of the journal Cell Metabolism under the title Dysfunctional Circadian Clock Accelerates Cancer Metastasis by Intestinal Microbiota Triggering Accumulation of Myeloid-Derived Suppressor Cells. The primary authors of the article include Jing-lin Liu, Xu Xu, Youlutuziayi Rixiati, and others, who are affiliated with the Department of Pathology at Sun Yat-sen Memorial Hospital, Sun Yat-sen University in Guangzhou, and the Department of Pathology at the Medical College of Soochow University, among other institutions. The corresponding authors are Tong Shen and Jian-ming Li.

Research Process and Experimental Methods

Detailed Description of Experimental Process

The experimental process of this study is as follows:

1. Preliminary Data Collection and Analysis:

   • Comparative transcriptomic analysis of primary tumors and distant metastases in CRC patients to reveal genes associated with myeloid cell activation and circadian rhythm.
   • Analysis of temperature oscillations in hospitalized CRC and lung cancer patients.

2. In Vitro Experiments:

   • Quantitative analysis of CD11b+, Bmal1+CD11b+, and Bmal1-CD11b+ immune cells in tumors and metastases of CRC patients using multiplex immunohistochemistry (MIHC).

3. In Vivo Model Establishment and Experiments:

   • Construction of a mouse model simulating social jet lag (CJ model) to observe the effect of circadian rhythm disruption on CRC lung metastasis.
   • Construction of CRC metastasis mouse models using Bmal1-/- and Per1-/-Per2-/- knockout mice of core circadian rhythm genes to analyze the effect of circadian rhythm on MDSCs and CD8+ T cell function.

4. Intestinal Microbiota and Metabolite Analysis:

   • Dynamic analysis of changes in intestinal microbes and their metabolites in circadian rhythm-disrupted mice using 16S DNA sequencing and targeted metabolomics.
   • Intestinal microbiota transplantation experiments to explore the role of intestinal microbiota in CRC metastasis under circadian rhythm disruption.

5. Molecular and Cellular Mechanism Studies:

   • Investigation of the specific regulatory mechanism of TCA (taurocholic acid) on glycolysis and immunosuppressive function of MDSCs, including the effect of TCA on H3K4 monomethylation and inhibition of CHIP (C-terminus of Hsc70 interacting protein)-mediated ubiquitination and degradation of PD-L1.

Novelty and Experimental Methods

This study is the first to reveal a novel mechanism by which circadian rhythm disruption mediates CRC metastasis and MDSCs accumulation through intestinal microbes and their metabolite TCA. The study utilizes a variety of experimental mouse models, combined with high-throughput transcriptomics, 16S DNA sequencing, and metabolomics analysis, to comprehensively elucidate the complex relationship between circadian rhythm and microbiota in cancer metastasis.

Research Results and Data Support

Major Research Findings

1. Circadian Rhythm Disruption and CRC Metastasis:

   • Myeloid cell activation and circadian rhythm-related genes were significantly upregulated in metastatic cases among CRC patients.
   • Temperature oscillation analysis of CRC patients showed that patients with distant metastases did not exhibit significant circadian rhythms, while non-metastatic patients had marked temperature oscillation rhythms.

2. Role of MDSCs:

   • The CJ model simulating social jet lag in mice showed that circadian rhythm disruption promoted the accumulation of MDSCs and PD-L1+ cells in the lungs.
   • Knockout of core circadian rhythm genes in Bmal1-/- and Per1-/-Per2-/- mice made them more susceptible to CRC lung metastasis.

3. Intestinal Microbiota and Metabolites:

   • Intestinal microbiota in circadian rhythm-disrupted mice exhibited loss of rhythm, with significant increases in key microbes such as Muribaculaceae and Akkermansia.
   • Intestinal microbiota transplantation experiments confirmed the critical role of intestinal microbiota in CRC metastasis under circadian rhythm disruption.

4. Molecular Mechanism and Role of TCA:

   • TCA promotes glycolysis and immunosuppressive function of MDSCs by enhancing H3K4 monomethylation and inhibiting CHIP-mediated ubiquitination and degradation of PD-L1.
   • Clinical sample analysis showed that TCA levels were significantly higher in CRC metastatic patients compared to non-metastatic patients and healthy individuals.

Research Conclusions and Value

This study reveals a novel mechanism by which circadian rhythm disruption promotes CRC metastasis and MDSCs accumulation through intestinal microbiota and its metabolite TCA. This finding provides a new perspective and potential targets for cancer treatment, especially in the application of circadian rhythm and lifestyle interventions. Fluorescent proteins or regulators such as TCA can be used as potential biomarkers for diagnosis and treatment.

Research Highlights

• This study is the first to reveal the interaction between circadian rhythm disruption, intestinal microbiota, and their metabolites in cancer metastasis.
• It elucidates the molecular mechanism by which TCA promotes the immunosuppressive function and glycolysis of MDSCs.
• It emphasizes the critical role of the central biological clock and the gut-immune cell axis in cancer metastasis.

This study not only provides a new perspective on understanding the complex relationship between circadian rhythm and cancer metastasis but also offers new ideas and potential targets for future cancer treatment strategies. The research underscores the importance of studying the relationship between the biological clock and diseases in the context of increasingly disrupted modern life rhythms.