{"title":"Pericyte drives the formation of circulating tumour cell-neutrophil clusters to promote colorectal cancer metastasis.","authors":"Sheng Wang,Geni Ye,Xiaoling Xu,Yuning Lin,Xiaobo Li,Zhang Zhang,Ming Qi,Lin Tan,Minjing Cheng,Haishan Zhang,Jinghua Pan,Changwei Lin,Dandan Huang,Rong Deng,Xiaomei Li,Guangsuo Wang,Shenghui Qiu,Xiaodong Chu,Yuhong Chen,Huhu Zeng,Junqiu Zhang,Chenran Wang,Hanlin Shuai,Changzheng Shi,Xia Yuan,Yihai Cao,Minfeng Chen,Maohua Huang,Wencai Ye,Dongmei Zhang","doi":"10.1136/gutjnl-2024-334618","DOIUrl":null,"url":null,"abstract":"BACKGROUND\r\nCirculating tumour cell (CTC)-neutrophil clusters represent a key driver and a hallmark of tumour metastasis; however, efficient approaches for their elimination are still lacking.\r\n\r\nOBJECTIVE\r\nThis study sought to elucidate the location and mechanisms of CTC-neutrophil cluster formation and develop more effective antimetastasis strategies.\r\n\r\nDESIGN\r\nImmunofluorescence 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.\r\n\r\nRESULTS\r\nCTC-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 NNMT-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.\r\n\r\nCONCLUSION\r\nThis 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.","PeriodicalId":12825,"journal":{"name":"Gut","volume":"711 1","pages":""},"PeriodicalIF":25.8000,"publicationDate":"2025-07-23","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"","citationCount":"0","resultStr":null,"platform":"Semanticscholar","paperid":null,"PeriodicalName":"Gut","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.1136/gutjnl-2024-334618","RegionNum":1,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q1","JCRName":"GASTROENTEROLOGY & HEPATOLOGY","Score":null,"Total":0}
引用次数: 0
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 NNMT-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.
期刊介绍:
Gut is a renowned international journal specializing in gastroenterology and hepatology, known for its high-quality clinical research covering the alimentary tract, liver, biliary tree, and pancreas. It offers authoritative and current coverage across all aspects of gastroenterology and hepatology, featuring articles on emerging disease mechanisms and innovative diagnostic and therapeutic approaches authored by leading experts.
As the flagship journal of BMJ's gastroenterology portfolio, Gut is accompanied by two companion journals: Frontline Gastroenterology, focusing on education and practice-oriented papers, and BMJ Open Gastroenterology for open access original research.