N6‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis
Abstract Background Gastric cancer peritoneal metastasis is clinically challenging, given the limited treatment options and poor prognosis. The molecular mechanisms that precede gastric cancer peritoneal metastasis, known as the pre‐metastatic niche (PMN), and its relationship with N6‐methyladenosin...
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Wiley
2025-08-01
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| Series: | Cancer Communications |
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| Online Access: | https://doi.org/10.1002/cac2.70034 |
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| author | Song Li Jianyuan Zhou Shuang Wang Qian Yang Shulun Nie Chunwang Ji Xue Zhang Shuhan Li Xuanyu Zhou Jiahui Chu Xuehui Wu Jianqiao Jiao Ruitao Xu Qian Xu Miao Huang Qiushi Wang Liliang Dou Qinqin Hu Fan Jiang Xin Dai Zhaodi Nan Xinyu Song Di Zhang Lian Liu |
| author_facet | Song Li Jianyuan Zhou Shuang Wang Qian Yang Shulun Nie Chunwang Ji Xue Zhang Shuhan Li Xuanyu Zhou Jiahui Chu Xuehui Wu Jianqiao Jiao Ruitao Xu Qian Xu Miao Huang Qiushi Wang Liliang Dou Qinqin Hu Fan Jiang Xin Dai Zhaodi Nan Xinyu Song Di Zhang Lian Liu |
| author_sort | Song Li |
| collection | DOAJ |
| description | Abstract Background Gastric cancer peritoneal metastasis is clinically challenging, given the limited treatment options and poor prognosis. The molecular mechanisms that precede gastric cancer peritoneal metastasis, known as the pre‐metastatic niche (PMN), and its relationship with N6‐methyladenosine (m6A) modification remain unclear. Methods We used 87 resected gastric cancer tissues and 4 public datasets to explore the association between methyltransferase‐like 3 (METTL3) expression and gastric cancer peritoneal metastasis. Roles of m6A, exosomes, or macrophages in PMN formation were explored in immunocompetent mouse models through exosome treatments or macrophage modifications. Key genes and regulatory mechanisms were uncovered using mass spectrometry, RNA/miRNA sequencing, RNA‐immunoprecipitation, dual‐luciferase assays, and point mutations in the ras‐related protein Rab‐27A (RAB27A) in cells. Macrophage and T‐cell functions were assessed using enzyme‐linked immunosorbent assay, flow cytometry, and cytotoxicity assays. Results METTL3 overexpression in gastric cancer cells enhanced RAB27A translation by methylating its mRNA A502 base, facilitated by its m6A “reader” YTH N6‐methyladenosine RNA binding protein F1 (YTHDF1), and led to increased exosome biogenesis. The miRNA‐17‐92 cluster was enriched in METTL3‐overexpressed cell‐derived exosomes and targeted SRC kinase signaling inhibitor 1 (SRCIN1) to activate SRC proto‐oncogene, non‐receptor tyrosine kinase (SRC) signaling in peritoneal macrophages. Macrophage activation skewed cytokine production towards an immunosuppressive profile in the peritoneum, elevating the levels of interleukin (IL)‐10 and tumor necrosis factor (TNF) and reducing the levels of IL‐1 and IL‐6. These cytokine shifts inhibited T cell proliferation and cytotoxic activities, which created an immunosuppressive PMN and led to peritoneal metastasis. The association between METTL3, macrophages, and peritoneal metastasis was verified in clinical samples. Conclusions Our study identified an intricate m6A‐regulated mechanism of peritoneal PMN development that is mediated by exosome‐promoted macrophages. These insights into gastric cancer peritoneal metastasis offer promising directions for translational research. |
| format | Article |
| id | doaj-art-421e6d1541a347aeb6d444648cabd0ec |
| institution | Kabale University |
| issn | 2523-3548 |
| language | English |
| publishDate | 2025-08-01 |
| publisher | Wiley |
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| series | Cancer Communications |
| spelling | doaj-art-421e6d1541a347aeb6d444648cabd0ec2025-08-20T08:40:33ZengWileyCancer Communications2523-35482025-08-0145894196510.1002/cac2.70034N6‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasisSong Li0Jianyuan Zhou1Shuang Wang2Qian Yang3Shulun Nie4Chunwang Ji5Xue Zhang6Shuhan Li7Xuanyu Zhou8Jiahui Chu9Xuehui Wu10Jianqiao Jiao11Ruitao Xu12Qian Xu13Miao Huang14Qiushi Wang15Liliang Dou16Qinqin Hu17Fan Jiang18Xin Dai19Zhaodi Nan20Xinyu Song21Di Zhang22Lian Liu23Department of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Pharmacy Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaDepartment of Medical Oncology Qilu Hospital, Cheeloo College of Medicine, Shandong University Jinan Shandong P. R. ChinaAbstract Background Gastric cancer peritoneal metastasis is clinically challenging, given the limited treatment options and poor prognosis. The molecular mechanisms that precede gastric cancer peritoneal metastasis, known as the pre‐metastatic niche (PMN), and its relationship with N6‐methyladenosine (m6A) modification remain unclear. Methods We used 87 resected gastric cancer tissues and 4 public datasets to explore the association between methyltransferase‐like 3 (METTL3) expression and gastric cancer peritoneal metastasis. Roles of m6A, exosomes, or macrophages in PMN formation were explored in immunocompetent mouse models through exosome treatments or macrophage modifications. Key genes and regulatory mechanisms were uncovered using mass spectrometry, RNA/miRNA sequencing, RNA‐immunoprecipitation, dual‐luciferase assays, and point mutations in the ras‐related protein Rab‐27A (RAB27A) in cells. Macrophage and T‐cell functions were assessed using enzyme‐linked immunosorbent assay, flow cytometry, and cytotoxicity assays. Results METTL3 overexpression in gastric cancer cells enhanced RAB27A translation by methylating its mRNA A502 base, facilitated by its m6A “reader” YTH N6‐methyladenosine RNA binding protein F1 (YTHDF1), and led to increased exosome biogenesis. The miRNA‐17‐92 cluster was enriched in METTL3‐overexpressed cell‐derived exosomes and targeted SRC kinase signaling inhibitor 1 (SRCIN1) to activate SRC proto‐oncogene, non‐receptor tyrosine kinase (SRC) signaling in peritoneal macrophages. Macrophage activation skewed cytokine production towards an immunosuppressive profile in the peritoneum, elevating the levels of interleukin (IL)‐10 and tumor necrosis factor (TNF) and reducing the levels of IL‐1 and IL‐6. These cytokine shifts inhibited T cell proliferation and cytotoxic activities, which created an immunosuppressive PMN and led to peritoneal metastasis. The association between METTL3, macrophages, and peritoneal metastasis was verified in clinical samples. Conclusions Our study identified an intricate m6A‐regulated mechanism of peritoneal PMN development that is mediated by exosome‐promoted macrophages. These insights into gastric cancer peritoneal metastasis offer promising directions for translational research.https://doi.org/10.1002/cac2.70034exosomesgastric cancerN6‐methyladenosineperitoneal metastasispre‐metastatic niche |
| spellingShingle | Song Li Jianyuan Zhou Shuang Wang Qian Yang Shulun Nie Chunwang Ji Xue Zhang Shuhan Li Xuanyu Zhou Jiahui Chu Xuehui Wu Jianqiao Jiao Ruitao Xu Qian Xu Miao Huang Qiushi Wang Liliang Dou Qinqin Hu Fan Jiang Xin Dai Zhaodi Nan Xinyu Song Di Zhang Lian Liu N6‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis Cancer Communications exosomes gastric cancer N6‐methyladenosine peritoneal metastasis pre‐metastatic niche |
| title | N6‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis |
| title_full | N6‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis |
| title_fullStr | N6‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis |
| title_full_unstemmed | N6‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis |
| title_short | N6‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis |
| title_sort | n6 methyladenosine regulated exosome biogenesis orchestrates an immunosuppressive pre metastatic niche in gastric cancer peritoneal metastasis |
| topic | exosomes gastric cancer N6‐methyladenosine peritoneal metastasis pre‐metastatic niche |
| url | https://doi.org/10.1002/cac2.70034 |
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