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58 SYNDECAN-1 Inhibition reverses the pre-malignant phenotype of endometrioma through TGF-BETA signalling: potential implications in endometriosis associated ovarian cancer

Objectives Transforming growth factor-beta (TGF-β) is abundantly expressed in peritoneal fluid and endometrioma of women with endometriosis. Similarly, transmembrane proteoglycans of the Syndecan family (SDC), act as co-receptors for growth signalling factors and are aberrantly expressed in endometriotic tissues. Here, we aim to investigate the regulation of SDC-1 upon induced activation with TGF-β in vitro, to better understand their interactions and involvement in the pathophysiology of endometriosis. Methods Endometrioma biopsies (n=15) were obtained from women diagnosed with endometriosis and not received any hormonal treatment. Tissue biospies were investigated for intra-patient heterogeneity using pre-validated panel of stem- and cancer- cell signalling genes. Simultaneously, patient-derived endometriotic stem/stromal cells (CD90+ CD73+CD105+, SC+) were allowed to generate 3D-spheroids in absence or presence of rhTGF-β or TGFBRI/II inhibitor Ly2109761 in vitro; assessed for its influence on SDC-1 expression, proliferation and invasive behaviour. Further, transcriptomic signatures after 3D-spheroid invasion was evaluated upon combining SDC-1 gene silencing with rhTGF-β treatment. Results Clustering analysis from endometriotic tissue gene expression revealed in 2/15 samples (referred to as Endo-hi) aberrant expression of molecules of TGF-β signalling (TGF-β1, ESR1, CTNNB1, SNAI1, BMI1) which grouped separately from low expression samples (Endo-lo) by >95% CI. 3D-spheroids from Endo-hi SC+ exposed to rhTGF-β treatment showed increased SDC-1 expression and higher 3D-spheroid invasion compared to Endo-lo SC+. However, rhTGFβ treatment following SDC-1 gene silencing reversed the higher 3D-invasion potential and exhibited downregulation of cancer associated pathways. Conclusions Modulation of SDC-1 reverses the pre-malignant phenotype of endometrioma and may reduce the potential risk for endometriosis associated ovarian cancer.