UGDH promotes tumor-initiating cells and a fibroinflammatory tumor microenvironment in ovarian cancer

Abstract

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, proteoglycan subunit synthesis enzyme UDP-glucose dehydrogenase (UGDH). Immunohistochemistry was used to delineate UGDH expression in histological and molecular subtypes of EOC. 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 C1/Mesenchymal subtype and low UGDH was associated with poor prognosis in the C4/Differentiated subtype. Ovarian cancer cell lines were subtyped according to the molecular subtypes, and we examined the effect of modulating UGDH expression in cell lines representing the C1/mesenchymal subtype the C4/Differentiated subtype. Knockdown of UGDH in the C1/Mesenchymal subtype reduced spheroid viability, sphere-formation and reduced the CD133+/ALDH high TIC population. Conversely, overexpression of UGDH in the differentiated subtype reduced the TIC population. Inflammatory cytokine expression was altered by UGDH expression. In co-culture models, altering UGDH expression in spheroids affected the gene expression of mesothelial cells causing changes to matrix remodeling proteins. The effect of UGDH knockdown or overexpression in the C1/ mesenchymal and C4/differentiated subtypes respectively was tested on mouse intrabursal xenografts and showed dynamic changes to the tumor stroma. Knockdown of UGDH reduced tumor burden in C1/mesenchymal compared to controls. These data show that modulation of UGDH expression in tumors influences cells in the microenvironment and reveals distinct roles for UGDH in the mesenchymal and differentiated molecular subtypes 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.

Pan-cancer analysis of UDP-glucose 6-dehydrogenase and its carcinogenesis in hepatocellular carcinoma

“…Previous studies have shown that UGDH is positively associated with the development of epirubicin resistance and regulation of the ECM in breast cancer [15]. Upregulation of UGDH has been associated with metastasis in ovarian cancer, where it regulates tumor-initiating cells affecting the tumor microenvironment [12]. And it may be related to melanoma development and progression [22].…”

“…The role of UGDH in cancer has received extensive attention from researchers in recent years. Abnormally elevated UGDH expression has been reported to be associated with the development of malignant tumors such as lung cancer [8], hepatocellular carcinoma (HCC) [9], pancreatic ductal adenocarcinoma [10], breast cancer [11], ovarian cancer [12], prostate cancer [13], and glioblastoma [14], as well as being correlated with poor prognosis of a variety of cancers. UGDH has broad and diverse regulatory effects in cancer and is closely associated with tumor drug resistance [15], epithelial-mesenchymal transition [16], and cellular localization [17], participating in pathways such as the sugar nucleotide biosynthetic [5] and TGFβ signaling [18] pathways, which is of great signi cance for cancer treatment.…”