Abstract IA5: Discovering the distal fallopian tube as the origin for high-grade serous ovarian cancer

Abstract

Abstract Recent developments in the study of epithelial ovarian cancer have called into question the traditional views regarding the site of tumor initiation. Histopathologic studies and genomic analyses suggest that extra-ovarian sites, like the fallopian tube (FT) epithelium, may harbor the coveted cell of origin and could therefore contribute significantly to the development of high-grade serous ovarian carcinoma (HGSOC). Our ability to validate these emerging genomic and pathologic observations and characterize the early transformation events of HGSOC hinges on the development of novel model systems. The tubal hypothesis of serous tumorigenesis has led us to develop a number of experimental platforms. These platforms provide us with a unique view into the susceptibilities of the FT epithelium to neoplastic transformation and provide a vehicle to query the contribution of any given genetic alteration to tumor development in vitro and in vivo. These models include the ex-vivo bioanalytical platform of benign FT epithelium, the in vitro FT secretory cell transformation model, a series of patient-derived primary tumor xenograft (PDX) models that retain the phenotypic and genotypic properties of the original patient tumors, and a genetically-engineered mouse model (GEMM) that specifically targets the FT epithelium in vivo. Our GEM model specifically targets the Müllerian secretory cell. It uses the Pax8 promoter to drive expression of the Cre recombinase in the fallopian tube (FT) secretory cells. Pax8 is a lineage marker for the Müllerian system. It is necessary for the development of the female reproductive tract and its expression is retained in the adult FT secretory cell and in nearly all HGSOCs. By crossing our Pax8-Cre deletor mouse with mice carrying floxed alleles of BRCA genes, TP53 (or mutant) and/or PTEN, we could specifically manipulate the expression of these genes in the FT secretory cell. Using this approach, in collaboration with the laboratory of Daniela Dinulescu, we showed that HGSOC can originate in secretory cell of the FT and also established that serous tubal intraepithelial carcinoma (STIC) is the precursor lesion to high-grade serous ovarian and peritoneal carcinomas. Importantly, the tumors that arise in this model not only look like high-grade serous carcinomas but they also retain the genomic complexity that is a hallmark of human HGSOC. In addition to providing mechanistic insight into the origin and pathogenesis of HGSC, this model provides a platform to explore HGSOC sensitivity to novel therapeutic strategies and to develop better detection strategies for early tumor diagnosis in high-risk women. Citation Format: Ronny Drapkin. Discovering the distal fallopian tube as the origin for high-grade serous ovarian cancer. [abstract]. In: Proceedings of the AACR Special Conference on Advances in Ovarian Cancer Research: From Concept to Clinic; Sep 18-21, 2013; Miami, FL. Philadelphia (PA): AACR; Clin Cancer Res 2013;19(19 Suppl):Abstract nr IA5.