Origins of Ovarian Carcinoma

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 DESCRIPTION (provided by applicant): Epithelial ovarian cancer (EOC) is the fifth leading cause of cancer death among women in the United States. Recent extensive integrated genomic analysis of high-grade serous ovarian adenocarcinomas has provided important insights about the repertoire of molecular aberrations characteristic for this, the most common and deadly, form of EOC. However, interpretation of the discovered aberrations is complicated because the cell of origin of this disease has not yet been unequivocally defined. Recently, we have identified the hilum region of the mouse ovary, the transitional/junction area between the ovarian surface epithelium (OSE), mesothelium and tubal (Fallopian or oviductal) epithelium as a previously unrecognized stem cell niche of the OSE. As we have shown, these cells express stem cell markers and display long-term stem cell properties ex vivo and in vivo, according to serial sphere generation and to long-term lineage tracing assays, respectively. Importantly, the hilar cells exhibit increased transformation potential after inactivation of tumor suppressor genes p53 (Trp53) and Rb (Rb1), pathways that are frequently altered in high grade serous adenocarcinoma. Our preliminary results indicate existence of stem cell niche in the mouse tubal epithelium, with a particular accumulation of cells in the most distal part of the uterine tue, near the tubal epithelium/mesothelium junction area. Notably both OSE and TE stem cell niches are characterized by high activity of the miR-34/MET network. Since OSE and tubal epithelium have a common origin from the coelomic epithelium both in mice and humans, we hypothesize that ovarian carcinomas arise from several developmentally connected stem cell niches within OSE/mesothelium/TE junction areas, where stem cells are more prone to transformation because of the innately active miR-34/MET network. To address this hypothesis we propose to (1) characterize a putative stem cell niche in the TE and establish its role in EOC formation, (2) perform comparative molecular characterization of OSE-SC and TE-SC niches, and (3) identify and characterize stem cell niches in human OSE and TE. It is expected that our work will provide critical missing links between clinical and experimental studies of ovarian carcinoma origin. Importantly, it should lead to identification of new diagnostic and prognostic markers and therapeutic targets.