Abstract GMM-018: CD73: A NEW DRIVER AND A THERAPEUTIC TARGET IN OVARIAN CANCER STEM CELLS

Abstract

Abstract Many biological and clinical features of ovarian cancer (OC) support the notion that the disease is driven by a subpopulation of self-renewing cancer stem cells (CSC) that are able to generate the entire progeny of short-lived, differentiated and heterogeneous cells that compose the tumor bulk. Ovarian cancer stem cells (OCSC), in particular, have been proposed to drive and sustain tumor dissemination, recurrence and chemoresistance, most likely due to their slow cycling rate and their detoxifying molecular machineries. This provides the rationale for investigating OCSC as suitable targets for OC eradication. Our study aims at assessing the functional contribution of OCSC to OC etiology and progression and at defining their molecular and functional traits. Specifically, we are pursuing these objectives through the accomplishment of the following milestones: 1) collection of normal and pathological samples; 2) identification of OCSC based on functional properties; 3) molecular profiling of OCSC and their normal counterpart; 4) characterization of novel genes/pathways involved in OCSC function (clonogenicity, tumorigenicity, quiescence, chemoresistance, etc.). We have established a repository of patient-derived primary cells isolated either from OC or from its tissues of origin, ovarian surface or fallopian tube epithelium. The OCSC subpopulation and their normal counterpart were then derived from primary cultures and used to profile their specific transcriptome, inferring a OCSC signature. Among the genes differentially expressed in OCSC, we focused on CD73, which encodes a membrane-associated 5'-ectonucleotidase that accounts for the generation of extracellular adenosine. Genetic ablation experiments revealed that CD73 acts as a driver of OC cell stemness and tumor initiation. Furthermore, the pharmacological inhibition of CD73 reduced OCSC self-renewal and tumorigenesis, highlighting the druggability of CD73 in the context of OCSC-directed therapies. The biological function of CD73 in OCSC required its enzymatic activity and involved adenosine signaling. Mechanistically, CD73 promotes the expression of stemness and epithelial-mesenchymal transition-associated genes, implying a regulation of OCSC function at the transcriptional level. In summary, CD73 is involved in OCSC biology and may represent a therapeutic target for innovative treatments aimed at OC eradication. In this context, CD73 is involved in tumor immune escape and actively investigated as a target to restore antitumor response. Thus, CD73-targeted therapies may combine the benefit of OCSC neutralization with overcoming CD73-driven immune escape, resulting in a synergistic effect towards OC eradication. Furthermore, CD73 neutralization might help preventing OCSC-dependent chemoresistance, thus enhancing the therapeutic efficacy of conventional chemotherapy. The therapeutic potential of CD73-based treatments and the molecular function of CD73 in OCSC are currently under investigation. Citation Format: Michela Lupia, Kris F. Sachsenmeier, Nicoletta Colombo, Fabrizio Bianchi, and Ugo Cavallaro. CD73: A NEW DRIVER AND A THERAPEUTIC TARGET IN OVARIAN CANCER STEM CELLS [abstract]. In: Proceedings of the 12th Biennial Ovarian Cancer Research Symposium; Sep 13-15, 2018; Seattle, WA. Philadelphia (PA): AACR; Clin Cancer Res 2019;25(22 Suppl):Abstract nr GMM-018.