N 6 ‐methyladenosine‐regulated exosome biogenesis orchestrates an immunosuppressive pre‐metastatic niche in gastric cancer peritoneal metastasis

作者：Li Song, Jianyuan Zhou, Shuang Wang, Qian Yang, Shulun Nie, Chunyan Ji, Xue Zhang, Shuhan Li, Xuanyu Zhou, Jiahui Chu, Xuehui Wu, Jianqiao Jiao, Ruitao Xu, Qian Xu, Miao Huang, Qiushi Wang, Liliang Dou, Qiao Hu, Fan Jiang, Xin Dai, Zhaodi Nan, Xinyu Song, Di Zhang, Lian Liu · 发表于：癌症：英文版 · 年份：2025 · DOI：10.1002/cac2.70034 · 被引用次数：16 · 研究领域：Extracellular vesicles in disease、Cancer-related molecular mechanisms research、Ferroptosis and cancer prognosis

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 N 6 ‐methyladenosine (m 6 A) 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 m 6 A, 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 m 6 A “reader” YTH N 6 ‐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...