Epithelial ovarian cancer (EOC) is a highly heterogeneous disease encompassing several distinct molecular subtypes and clinical entities. Despite the initial success of surgical debulking and adjuvant chemotherapy, recurrence with chemotherapy resistant tumors is common in patients with EOC and leads to poor overall survival. The extensive genetic and phenotypic heterogeneity associated with ovarian cancers has hindered the identification of effective prognostic and predictive biomarkers in EOC patients. In the current studies, we identify a tumor cell surface oncoantigen, chondroitin sulfate proteoglycan 4 (CSPG4), as an independent risk factor for decreased survival of patients with EOC. Our results show that CSPG4 promotes EOC cell invasion, cisplatin resistance and spheroid formation in vitro and tumor expansion in vivo. Mechanistically, spheroid formation and tumor cell invasion are due to CSPG4-stimulated expression of the mesenchymal transcription factor ZEB1. Furthermore, we have developed a novel monoclonal anti-CSGP4 antibody against the juxtamembrane domain of the core protein that limits CSPG4-stimulated ZEB1 expression, tumor cell invasion and promotes EOC apoptosis within spheroid cultures. We therefore propose that CSPG4 expression drives phenotypic heterogeneity and malignant progression in EOC tumors. These studies further demonstrate that CSPG4 expression levels are a potential diagnostic biomarker in EOC and indicate that targeting cells which express this oncoantigen could limit recurrence and improve outcomes in patients with EOC.
Bibliographical noteFunding Information:
This work was supported by NCI grants P01 CA111412 and R35 CA197292 awarded to J.S.M, grants from the National Natural Science Foundation of China ( 81972836 ) and the Science and Technology Innovation Program of Hunan Province (2020SK2120) awarded to J. W. and Q.L. Additional funding was provided by the Atwater Fund, Elsa Pardee and Chairman's Fund Professor in Cancer Research to J.B.M. T.K.S was supported by grants from Minnesota Ovarian Cancer Alliance, the Randy Shaver Cancer Research and Community Fund, and the University of Minnesota Grand Challenges. A.C.N is supported by the American Cancer Society 132574-CSDG-18-139-01-CSM . The authors also acknowledge the Imaging Core and the Flow Cytometry Core at the University of Minnesota for their excellent service. The authors have declared that no conflict of interest exists.