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In an in vivo LNM model, MEOX1 overexpression enhances tumor burden, lymphatic vessel density, and LNM, whereas tumor\u2010conditioned medium does not directly activate lymphatic endothelial cells (LECs), implicating stromal intermediates. Spatial transcriptomic and immunostaining analyses confirmed cancer\u2010associated fibroblast (CAF)\u2010LEC proximity and vascular endothelial growth factor\u2010C (VEGF\u2010C) localization within CAFs, supporting a CAF\u2010dependent lymphangiogenic route. Mechanistically, MEOX1 binds the sphingosine kinase 1 (SPHK1) promoter to activate sphingosine\u20101\u2010phosphate (S1P) synthesis, driving a dual autocrine\u2010paracrine program: sphingosine\u20101\u2010phosphate receptor 3 (S1PR3)\u2010dependent signaling promotes tumor proliferation\/migration, while S1P\/S1PR1 reprograms fibroblasts into VEGF\u2010C\u2010secreting, alpha\u2010smooth muscle actin (\u03b1\u2010SMA)\u2010positive CAFs that stimulate lymphangiogenesis and LNM; SPHK1 inhibition blunts these phenotypes, whereas S1P supplementation restores them. These findings provide novel insights into lymphatic metastasis and demonstrate that metastatic competence depends not only on intrinsic tumor aggressiveness but also on the acquired ability to construct a pro\u2010dissemination niche.<\/jats:p>","DOI":"10.1002\/advs.202523574","type":"journal-article","created":{"date-parts":[[2026,5,10]],"date-time":"2026-05-10T18:07:52Z","timestamp":1778436472000},"update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["MEOX1 Coordinates Autocrine\u2010Paracrine Programs via SPHK1\/S1P to Promote Lymph Node Metastasis in Ovarian Cancer"],"prefix":"10.1002","volume":"13","author":[{"given":"Jiajia","family":"Li","sequence":"first","affiliation":[{"name":"Department of Gynecologic Oncology Obstetrics &amp; Gynecology Hospital of Fudan University Shanghai Key Lab of Reproduction and Development Shanghai Key Lab of Female Reproductive Endocrine Related Diseases  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Xiuling","family":"Zhi","sequence":"additional","affiliation":[{"name":"Department of Physiology and Pathophysiology, School of Basic Medical Sciences Fudan University  Shanghai China"}],"role":[{"vocabulary":"crossref","role":"author"}]},{"given":"Qianhan","family":"Lin","sequence":"additional","affiliation":[{"name":"Department of Gynecologic Oncology Obstetrics &amp; 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