Abstract 1553: S1PR1 directs tumorsphere proliferation in ovarian cancer

Abstract Despite the clinical efforts to improve detection and treatment of high-grade serous ovarian cancer (HGSOC), half of diagnosed women will die every year because of this disease. Notably, nearly all of them present with ascites at diagnosis, which is directly associated with poor prognosis. Malignant ascites production occurs when ovarian cancer cells shed from the primary tumor, creating a selective pressure environment that threatens their survival. Therefore, cancer cells cluster into tumorspheres, the main metastatic units in HGSOC. In recent years, valuable insights into the mutational and immunological landscapes of HGSOC have been gained. However, there is scarce evidence on the precise molecular mechanisms that enable tumorspheres to surpass the ascites bottleneck and metastasize. In this work, our group addresses this knowledge gap by deciphering the role of S1PR1 in ovarian tumorsphere biology. In this study, ascites samples and Formalin-Fixed Paraffin-Embedded (FFPE) tumors and peritoneal metastases from a cohort of 32 treatment-naïve HGSOC patients have been used. Furthermore, 3D spheroid models from four different ovarian cancer cell lines have also been developed for in vitro and in vivo assays. Our results indicate that up to 60% of cells within HGSOC tumorspheres are proliferating due to an increased expression of pro-proliferative receptors. Thus, cancer cells within tumorspheres that overexpress these receptors might benefit from autocrine and paracrine signaling through release of their ligands. In this work, we have identified S1P-S1PR1 as one of these ligand-receptor axes, which promotes an autocrine positive loop that increases the intermediates of sphingolipid metabolism in ovarian cancer spheroids. Here, we demonstrate that S1PR1 is highly expressed in ascites tumorspheres and, in consequence, overexpressed in metastases in comparison with primary tumors. Furthermore, we also report that proliferation levels of ovarian cancer spheroids positively correlate with S1PR1 endogenous expression. Consistently, these levels are significantly reduced when S1PR1 is knocked out or pharmacologically inhibited. In addition, our results indicate that MEK1/2-ERK is the key downstream pro-mitogenic pathway of S1PR1 in HGSOC tumorspheres, and that its pharmacological inhibition is effective in reducing growth and number of disseminations in vivo. Conclusively, our group is the first one in reporting that the axis S1P-S1PR1-MEK1/2 is the main proliferative mechanism in HGSOC tumorspheres, providing them with a selective advantage and, consequently, a greater metastatic potential. The preclinical findings presented here may represent an opportunity to further explore targeted therapeutic strategies to hamper disease progression in ovarian cancer patients with the poorest outcome. Citation Format: Núria Gendrau-Sanclemente, Agnès Figueras, Kristina Gracova, Elisenda Alsina-Sanchís, Juan Antonio Marín-Jiménez, Josefina Casas, August Vidal, Xavier Matias-Guiu, Sergi Fernandez-Gonzalez, Marc Barahona, Lola Martí, Jordi Ponce, Francesc Viñals. S1PR1 directs tumorsphere proliferation in ovarian cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1553.