{
  "abstract": "Background Circulating tumour cell (CTC)-neutrophil clusters represent a key driver and a hallmark of tumour metastasis; however, efficient approaches for their elimination are still lacking.Objective This study sought to elucidate the location and mechanisms of CTC-neutrophil cluster formation and develop more effective antimetastasis strategies.Design Immunofluorescence staining of clinical colorectal cancer (CRC) samples was performed to identify the location of CTC-neutrophil clusters. The correlation between the expression of nicotinamide N-methyltransferase (NNMT) in pericytes and patient prognosis, as well as its association with CTC-neutrophil cluster formation, was assessed using clinical specimens and public CRC datasets. The formation process of CTC-neutrophil clusters was visualised using intravital microscope and microfluidic vascular chip models. Bulk RNA sequencing, xenograft and allograft models and pericyte-specific genetic Nnmt deficiency mice were used to investigate the effect of pericyte NNMT on CTC-neutrophil cluster formation and CRC metastasis.Results CTC-neutrophil clusters formed at the vascular-immune interface of CRC primary tumours. Pericytes with high NNMT expression could serve as a poor prognostic biomarker that indicated an increased risk of developing metastasis in CRC. NNMT highly expressing pericytes facilitated the formation of CTC-neutrophil clusters by mediating the cellular interaction among CRC cells, neutrophils and endothelial cells through activating the CXCL5/CXCR2 axis. Genetic and pharmacological inhibition of NNMT in pericytes eliminated CTC-neutrophil clusters and suppressed CRC liver metastasis.Conclusion This study uncovers the previously undefined location and mechanism of CTC-neutrophil cluster formation and underscores the potential of pericyte-driven CTC-neutrophil clusters as a valuable prognostic indicator and therapeutic target for CRC metastasis.",
  "authors": [
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China",
        "The Fifth Affiliated Hospital of Jinan University, Heyuan, Guangdong, China"
      ],
      "name": "Sheng Wang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Geni Ye"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Xiaoling Xu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Yuning Lin"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Xiaobo Li"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Zhang Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Ming Qi"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Lin Tan"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Minjing Cheng"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Haishan Zhang"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Jinghua Pan"
    },
    {
      "affiliations": [
        "Department of Gastrointestinal Surgery, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China"
      ],
      "name": "Changwei Lin"
    },
    {
      "affiliations": [
        "Department of General Surgery (anal surgery), Guangdong Provincial Key Laboratory of Colorectal and Pelvic Floor Diseases, The Sixth Affiliated Hospital, Sun Yat-sen University, Guangzhou, Guangdong, China"
      ],
      "name": "Dandan Huang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China"
      ],
      "name": "Rong Deng"
    },
    {
      "affiliations": [
        "Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University",
        "The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China"
      ],
      "name": "Xiaomei Li"
    },
    {
      "affiliations": [
        "Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University",
        "The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, Guangdong, China"
      ],
      "name": "Guangsuo Wang"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Shenghui Qiu"
    },
    {
      "affiliations": [
        "The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Xiaodong Chu"
    },
    {
      "affiliations": [
        "State Key Laboratory of Oncology in South China, Collaborative Innovation Center for Cancer Medicine, Guangdong Key Laboratory of Nasopharyngeal Carcinoma Diagnosis and Therapy, Sun Yat-sen University Cancer Center, Guangzhou, Guangdong, China"
      ],
      "name": "Yuhong Chen"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Huhu Zeng"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Junqiu Zhang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Chenran Wang"
    },
    {
      "affiliations": [
        "The Fifth Affiliated Hospital of Jinan University, Heyuan, Guangdong, China",
        "The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Hanlin Shuai"
    },
    {
      "affiliations": [
        "The Fifth Affiliated Hospital of Jinan University, Heyuan, Guangdong, China",
        "The First Affiliated Hospital of Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Changzheng Shi"
    },
    {
      "affiliations": [
        "Department of Medical Oncology, Huizhou First Hospital, Huizhou, Guangdong, China"
      ],
      "name": "Xia Yuan"
    },
    {
      "affiliations": [
        "Department of Microbiology, Tumor and Cell Biology, Karolinska Institutet, Stockholm, Sweden"
      ],
      "name": "Yihai Cao"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Minfeng Chen"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Maohua Huang"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Wencai Ye"
    },
    {
      "affiliations": [
        "State Key Laboratory of Bioactive Molecules and Druggability Assessment, Guangdong Basic Research Center of Excellence for Natural Bioactive Molecules and Discovery of Innovative Drugs, Jinan University, Guangzhou, Guangdong, China",
        "College of Pharmacy, Jinan University, Guangzhou, Guangdong, China",
        "Guangdong-Hong Kong-Macau Joint Laboratory for Pharmacodynamic Constituents of TCM and New Drugs Research, Guangdong Province Key Laboratory of Pharmacodynamic Constituents of TCM and New Drugs Research, Jinan University, Guangzhou, Guangdong, China"
      ],
      "name": "Dongmei Zhang"
    }
  ],
  "title": "Pericyte drives the formation of circulating tumour cell-neutrophil clusters to promote colorectal cancer metastasis",
  "uid": "89a54e1c-fa8e-56c7-b9a1-d9221d7b97e0"
}