Epithelial ovarian cancer (EOC) is a global health burden, with the poorest five-year survival rate of the gynecological malignancies due to diagnosis at advanced stage and high recurrence rate. Recurrence in EOC is driven by the survival of chemoresistant, stem-like tumor-initiating cells (TICs) that are supported by a complex extracellular matrix (ECM) and immunosuppressive microenvironment. To target TICs to prevent recurrence, we identified genes critical for TIC viability from a whole genome siRNA screen. A top hit was the cancer-associated, ECM synthesis enzyme UDP-glucose dehydrogenase (UGDH). Immunohistochemistry was used to delineate UGDH expression in histological and molecular subtypes of EOC. Clustering analysis was performed to characterize EOC cell lines to aligned to the molecular subtypes observed in tumors. UGDH expression was modulated in the cell lines using inducible shRNA, and the effects on TICs and on the cells in the supporting microenvironment were examined. High UGDH expression was observed in the majority of high-grade serous ovarian cancers and variable expression was observed in clear cell, mucinous and endometrioid histotypes. A distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype, where high UGDH was associated with a poor prognosis in the mesenchymal subtype. Using OV90 as a representative cell line for the mesenchymal subtype, we examined the effect of UGDH knockdown on the tumor cells alone, and on mesothelial support cells in co-culture with the tumor cells. Knock down of UGDH in the OV90 cells reduced the viability, sphere-formation and colony formation capacity of TICs and reduced extracellular hyaluronan production. Knocking down UGDH in the tumors affected the mesothelial cells in co-culture by significantly reducing the expression of ECM signaling and remodeling proteins Versican, Vitronectin, Laminin and matrix metalloprotease 1. These data show that modulation of UGDH expression in tumors influences cells in the microenvironment and reveal a distinct role for UGDH in the mesenchymal molecular subtype of EOC. UGDH is a strong prospective therapeutic target in TICs, for the treatment of metastatic and recurrent EOC, particularly in patients with the mesenchymal molecular subtype.
Citation Format: Brittney S. Harrington, Rahul Kamdar, Nathan Wong, Carrie D. House, Christina M. Annunziata. Modulating UGDH expression in ovarian cancer tumor-initiating cells alters the tumor microenvironment [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 3188.