MEOX1 Coordinates Autocrine‐Paracrine Programs via SPHK1/S1P to Promote Lymph Node Metastasis in Ovarian Cancer

ABSTRACT Lymph node metastasis (LNM) is a pivotal determinant of poor prognosis in ovarian cancer (OC), yet how tumor‐intrinsic programs remodel the microenvironment to enable spread remains unclear.Here, we identify the transcription factor mesenchymal homeobox 1 (MEOX1) as an upstream coordinator, whose overexpression associates with LNM, increased lymphatic density, and poor survival based on integrative analyses of public datasets and our 113‐patient cohort. In an in vivo LNM model, MEOX1 overexpression enhances tumor burden, lymphatic vessel density, and LNM, whereas tumor‐conditioned medium does not directly activate lymphatic endothelial cells (LECs), implicating stromal intermediates. Spatial transcriptomic and immunostaining analyses confirmed cancer‐associated fibroblast (CAF)‐LEC proximity and vascular endothelial growth factor‐C (VEGF‐C) localization within CAFs, supporting a CAF‐dependent lymphangiogenic route. Mechanistically, MEOX1 binds the sphingosine kinase 1 (SPHK1) promoter to activate sphingosine‐1‐phosphate (S1P) synthesis, driving a dual autocrine‐paracrine program: sphingosine‐1‐phosphate receptor 3 (S1PR3)‐dependent signaling promotes tumor proliferation/migration, while S1P/S1PR1 reprograms fibroblasts into VEGF‐C‐secreting, alpha‐smooth muscle actin (α‐SMA)‐positive 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‐dissemination niche.