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

作者：Brittney S. Harrington, Rahul Kamdar, Franklin Ning, Soumya Korrapati, Michael W. Caminear, Lídia Hernandez, Donna Butcher, Elijah F. Edmondson, Nadia Traficante, Joy Hendley, Australian Ovarian Cancer Study, Madeline Gough, Rebecca F. Rogers, Rohan Lourie, Jyoti Shetty, Bao Tran, Fathi Elloumi, Abdalla Abdelmaksoud, Madhu Lal Nag, Krystyna Mazan-Mamczarz, Carrie D. House, John D. Hooper, Christina M. Annunziata · 发表于：Journal of Experimental & Clinical Cancer Research · 年份：2023 · DOI：10.1186/s13046-023-02820-z · 被引用次数：16 · 研究领域：Cancer, Hypoxia, and Metabolism、Cancer Cells and Metastasis、Proteoglycans and glycosaminoglycans research

Abstract Background 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 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). Methods Immunohistochemistry was used to characterize UGDH expression in histological and molecular subtypes of EOC. EOC cell lines were subtyped according to the molecular subtypes and the functional effects of modulating UGDH expression in vitro and in vivo in C1/Mesenchymal and C4/Differentiated subtype cell lines was examined. Results High UGDH expression was observed in high-grade serous ovarian cancers and a distinctive survival prognostic for UGDH expression was revealed when serous cancers were stratified by molecular subtype. 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. Knockdown of UGDH in the C1/mesenchymal molecular subtype reduced spheroid formation and viability and reduced the CD133 + /ALDH high TIC population. Conversely,...