{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,9,8]],"date-time":"2026-09-08T15:20:23Z","timestamp":1788880823741,"version":"build-2803163510"},"reference-count":61,"publisher":"American Association for the Advancement of Science (AAAS)","issue":"8","license":[{"start":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T00:00:00Z","timestamp":1747267200000},"content-version":"vor","delay-in-days":0,"URL":"http:\/\/creativecommons.org\/licenses\/by-nc-nd\/4.0\/"}],"funder":[{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173305"],"award-info":[{"award-number":["82173305"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100001809","name":"National Natural Science Foundation of China","doi-asserted-by":"publisher","award":["82173305"],"award-info":[{"award-number":["82173305"]}],"id":[{"id":"10.13039\/501100001809","id-type":"DOI","asserted-by":"publisher"}]},{"DOI":"10.13039\/501100007129","name":"Natural Science Foundation of Shandong Province","doi-asserted-by":"publisher","award":["ZR2023LSW018"],"award-info":[{"award-number":["ZR2023LSW018"]}],"id":[{"id":"10.13039\/501100007129","id-type":"DOI","asserted-by":"publisher"}]}],"content-domain":{"domain":["onlinelibrary.wiley.com"],"crossmark-restriction":true},"short-container-title":["Cancer Commun"],"published-print":{"date-parts":[[2025,8]]},"abstract":"<jats:title>Abstract<\/jats:title>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Background<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      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\u2010metastatic niche (PMN), and its relationship with\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      <jats:sup>6<\/jats:sup>\n                      \u2010methyladenosine (m\n                      <jats:sup>6<\/jats:sup>\n                      A) modification remain unclear.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Methods<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      We used 87 resected gastric cancer tissues and 4 public datasets to explore the association between methyltransferase\u2010like 3 (METTL3) expression and gastric cancer peritoneal metastasis. Roles of m\n                      <jats:sup>6<\/jats:sup>\n                      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\u2010immunoprecipitation, dual\u2010luciferase assays, and point mutations in the ras\u2010related protein Rab\u201027A (\n                      <jats:italic toggle=\"yes\">RAB27A<\/jats:italic>\n                      ) in cells. Macrophage and T\u2010cell functions were assessed using enzyme\u2010linked immunosorbent assay, flow cytometry, and cytotoxicity assays.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Results<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      METTL3 overexpression in gastric cancer cells enhanced\n                      <jats:italic toggle=\"yes\">RAB27A<\/jats:italic>\n                      translation by methylating its mRNA A502 base, facilitated by its m\n                      <jats:sup>6<\/jats:sup>\n                      A \u201creader\u201d YTH\n                      <jats:italic toggle=\"yes\">N<\/jats:italic>\n                      <jats:sup>6<\/jats:sup>\n                      \u2010methyladenosine RNA binding protein F1 (YTHDF1), and led to increased exosome biogenesis. The miRNA\u201017\u201092 cluster was enriched in METTL3\u2010overexpressed cell\u2010derived exosomes and targeted SRC kinase signaling inhibitor 1 (SRCIN1) to activate SRC proto\u2010oncogene, non\u2010receptor 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)\u201010 and tumor necrosis factor (TNF) and reducing the levels of IL\u20101 and IL\u20106. 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.\n                    <\/jats:p>\n                  <\/jats:sec>\n                  <jats:sec xml:lang=\"en\">\n                    <jats:title>Conclusions<\/jats:title>\n                    <jats:p xml:lang=\"en\">\n                      Our study identified an intricate m\n                      <jats:sup>6<\/jats:sup>\n                      A\u2010regulated mechanism of peritoneal PMN development that is mediated by exosome\u2010promoted macrophages. These insights into gastric cancer peritoneal metastasis offer promising directions for translational research.\n                    <\/jats:p>\n                  <\/jats:sec>","DOI":"10.1002\/cac2.70034","type":"journal-article","created":{"date-parts":[[2025,5,15]],"date-time":"2025-05-15T04:31:34Z","timestamp":1747283494000},"page":"941-965","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":21,"title":["<i>N<\/i>\n                    <sup>6<\/sup>\n                    \u2010methyladenosine\u2010regulated exosome biogenesis orchestrates an immunosuppressive pre\u2010metastatic niche in gastric cancer peritoneal metastasis"],"prefix":"10.34133","volume":"45","author":[{"given":"Song","family":"Li","sequence":"first","affiliation":[{"name":"Qilu Hospital, Cheeloo College of Medicine, Shandong University","place":["Jinan, P. R. 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