NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion
Abstract The relationship between patterns of RNA modifications and gastric cancer (GC) liver metastasis (GCLM) remains unclear. Here, by single‐cell sequencing, clinical sample analysis, and mouse model studies, an abnormal increase in the expression of the RNA acetyltransferase N‐acetyltransferase...
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| Format: | Article |
| Language: | English |
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Wiley
2025-04-01
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| Series: | Advanced Science |
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| Online Access: | https://doi.org/10.1002/advs.202410263 |
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| author | Chen Chen Zhangding Wang Qingfeng Lin Mengmeng Li Lei Xu Yao Fu Xiaoya Zhao Zhuang Ma Jiawen Xu Shimeng Zhou Mingyue Zhang Yun Qian Linsen Bao Bo Wang Meng Wang Qingqing Ding Qiang Wang Shouyu Wang |
| author_facet | Chen Chen Zhangding Wang Qingfeng Lin Mengmeng Li Lei Xu Yao Fu Xiaoya Zhao Zhuang Ma Jiawen Xu Shimeng Zhou Mingyue Zhang Yun Qian Linsen Bao Bo Wang Meng Wang Qingqing Ding Qiang Wang Shouyu Wang |
| author_sort | Chen Chen |
| collection | DOAJ |
| description | Abstract The relationship between patterns of RNA modifications and gastric cancer (GC) liver metastasis (GCLM) remains unclear. Here, by single‐cell sequencing, clinical sample analysis, and mouse model studies, an abnormal increase in the expression of the RNA acetyltransferase N‐acetyltransferase 10 (NAT10) in liver metastatic GC cells is identified. NAT10‐mediated N4‐acetylcytidine modification of CXCL2 and KLF5 mRNA increases their stability. Then, secreted CXCL2 is found to promote the infiltration and polarization of M2‐like macrophages to produce oncostatin M, which transcriptionally activates NAT10 expression via STAT3 signaling. In addition, organoid models confirm that NAT10 promotes the adhesion of GC cells to hepatocytes. Mechanistically, KLF5 transcriptionally activates ITGαV, facilitating GC cell attachment to hepatocytes. Intriguingly, high expression of NAT10/KLF5 axis is associated with poor prognosis of GC patients and targeting this axis significantly reduces GCLM in preclinical murine models. Collectively, these findings suggest the clinical significance of NAT10 in developing targeted therapies for GC patients with liver metastasis. |
| format | Article |
| id | doaj-art-94e3e5f0e2a54c1d8347f20b190b68d0 |
| institution | DOAJ |
| issn | 2198-3844 |
| language | English |
| publishDate | 2025-04-01 |
| publisher | Wiley |
| record_format | Article |
| series | Advanced Science |
| spelling | doaj-art-94e3e5f0e2a54c1d8347f20b190b68d02025-08-20T03:18:05ZengWileyAdvanced Science2198-38442025-04-011215n/an/a10.1002/advs.202410263NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic AdhesionChen Chen0Zhangding Wang1Qingfeng Lin2Mengmeng Li3Lei Xu4Yao Fu5Xiaoya Zhao6Zhuang Ma7Jiawen Xu8Shimeng Zhou9Mingyue Zhang10Yun Qian11Linsen Bao12Bo Wang13Meng Wang14Qingqing Ding15Qiang Wang16Shouyu Wang17Department of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor Immunotherapy Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy Hefei 230022 ChinaDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor Immunotherapy Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy Hefei 230022 ChinaDepartment of Oncology Jiangyin Clinical College of Xuzhou Medical University Jiangyin Hospital Affiliated to Nantong University Jiangyin People's Hospital Jiangyin 214400 ChinaMedical School of Nanjing University Nanjing 210093 ChinaDepartment of Gastroenterology The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing 210008 ChinaDepartment of Pathology The First Affiliated Hospital of Anhui Medical University Hefei 230022 ChinaMedical School of Nanjing University Nanjing 210093 ChinaMedical School of Nanjing University Nanjing 210093 ChinaMedical School of Nanjing University Nanjing 210093 ChinaMedical School of Nanjing University Nanjing 210093 ChinaMedical School of Nanjing University Nanjing 210093 ChinaMedical School of Nanjing University Nanjing 210093 ChinaDivision of Gastric Surgery Department of General Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing 210008 ChinaDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor Immunotherapy Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy Hefei 230022 ChinaDivision of Gastric Surgery Department of General Surgery The Affiliated Drum Tower Hospital of Nanjing University Medical School Nanjing 210008 ChinaDepartment of Geriatric Oncology The First Affiliated Hospital of Nanjing Medical University Nanjing 210029 ChinaDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor Immunotherapy Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy Hefei 230022 ChinaDepartment of Hepatobiliary Surgery, The First Affiliated Hospital of Anhui Medical University; MOE Innovation Center for Basic Research in Tumor Immunotherapy Anhui Province Key Laboratory of Tumor Immune Microenvironment and Immunotherapy Hefei 230022 ChinaAbstract The relationship between patterns of RNA modifications and gastric cancer (GC) liver metastasis (GCLM) remains unclear. Here, by single‐cell sequencing, clinical sample analysis, and mouse model studies, an abnormal increase in the expression of the RNA acetyltransferase N‐acetyltransferase 10 (NAT10) in liver metastatic GC cells is identified. NAT10‐mediated N4‐acetylcytidine modification of CXCL2 and KLF5 mRNA increases their stability. Then, secreted CXCL2 is found to promote the infiltration and polarization of M2‐like macrophages to produce oncostatin M, which transcriptionally activates NAT10 expression via STAT3 signaling. In addition, organoid models confirm that NAT10 promotes the adhesion of GC cells to hepatocytes. Mechanistically, KLF5 transcriptionally activates ITGαV, facilitating GC cell attachment to hepatocytes. Intriguingly, high expression of NAT10/KLF5 axis is associated with poor prognosis of GC patients and targeting this axis significantly reduces GCLM in preclinical murine models. Collectively, these findings suggest the clinical significance of NAT10 in developing targeted therapies for GC patients with liver metastasis.https://doi.org/10.1002/advs.202410263cell adhesiongastric cancerliver metastasismacrophage polarizationNAT10 |
| spellingShingle | Chen Chen Zhangding Wang Qingfeng Lin Mengmeng Li Lei Xu Yao Fu Xiaoya Zhao Zhuang Ma Jiawen Xu Shimeng Zhou Mingyue Zhang Yun Qian Linsen Bao Bo Wang Meng Wang Qingqing Ding Qiang Wang Shouyu Wang NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion Advanced Science cell adhesion gastric cancer liver metastasis macrophage polarization NAT10 |
| title | NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion |
| title_full | NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion |
| title_fullStr | NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion |
| title_full_unstemmed | NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion |
| title_short | NAT10 Promotes Gastric Cancer Liver Metastasis by Modulation of M2 Macrophage Polarization and Metastatic Tumor Cell Hepatic Adhesion |
| title_sort | nat10 promotes gastric cancer liver metastasis by modulation of m2 macrophage polarization and metastatic tumor cell hepatic adhesion |
| topic | cell adhesion gastric cancer liver metastasis macrophage polarization NAT10 |
| url | https://doi.org/10.1002/advs.202410263 |
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