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Significantly, nearly all HGSOC cases manifest ascites at diagnosis, a poor prognostic indicator. Malignant ascites production arises as ovarian cancer cells shed from the primary tumor, creating a new environment that challenges their survival. Consequently, cancer cells aggregate into tumorspheres, the principal metastatic units in HGSOC. The molecular mechanisms that tumorspheres use to overcome the ascites bottleneck and metastasize are still poorly understood. Studying tumorspheres isolated from ascites samples from treatment na\u00efve HGSOC patients, as well as three\u2010dimensional spheroid in\u00a0vitro and in\u00a0vivo ovarian cancer cell models, we report that the sphingosine\u20101\u2010phosphate (S1P) ligand and its receptor S1PR1 axis is especially relevant in ovarian tumorspheres, where it promotes an autocrine positive loop, serving as their primary proliferative mechanism via MEK1\/2\u2010ERK activation. Our findings demonstrate that the S1P\u2010S1PR1\u2010MEK1\/2 pathway confers ovarian tumorspheres a selective advantage within the ascites environment and, consequently, increases their metastatic potential.<\/jats:p>","DOI":"10.1002\/ijc.70467","type":"journal-article","created":{"date-parts":[[2026,4,10]],"date-time":"2026-04-10T05:22:31Z","timestamp":1775798551000},"page":"768-781","update-policy":"https:\/\/doi.org\/10.1002\/crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Sphingosine\u20101\u2010Phosphate Receptor 1 Promotes Ovarian Cancer Tumorsphere Proliferation and Metastasis"],"prefix":"10.1002","volume":"159","author":[{"given":"N\u00faria","family":"Gendrau\u2010Sanclemente","sequence":"first","affiliation":[{"name":"Program Against Cancer Therapeutic Resistance (ProCURE), Catalan Institute of Oncology (ICO) Hospital Duran i Reynals  L'Hospitalet de Llobregat, Barcelona Spain"},{"name":"Oncobell Program Institut Ddinvestigaci\u00f3 Biom\u00e8dica 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