Abstract PR01: Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in BRCA/P53 models
Authors: Wyant Gregory A , Perets Ruth , Muto Katherine , Poole Barish B. , Chen Jin YH , Ohman Anders W , Setlur Sunita R , Crum Christopher P. , Drapkin Ronny , Dinulescu Daniela M. 
Published: August 2014

Abstract
High-grade serous ovarian cancer, the most common and deadly subtype of ovarian tumors, presents significant clinical and therapeutic challenges. Effective tools for early detection are not readily available resulting in late diagnosis of often widely metastatic disease. Although research has traditionally focused on the hypothesis that HGSC arises from the ovarian surface epithelium (OSE) or ovarian inclusion cysts, recent studies from BRCA1 and BRCA2 mutation carriers undergoing prophylactic salpingo-oophorectomies suggest that additional sites of origin exist and a substantial proportion of cases may arise instead from precursor lesions located in the fallopian tubal epithelium (FTE). The latter hypothesis is based on the detection of pre-invasive lesions, namely serous tubal intraepithelial carcinomas (STIC), found in the fallopian tubes (FT) of both women at high-risk for developing serous carcinomas as well as patients with disseminated HGSCs. Recent studies of ovarian and tubal tissue samples from high-risk BRCA1/2 carriers who underwent prophylactic salpingo-oophorectomy procedures to reduce cancer risk revealed early cancer lesions in ~5-15% of cases, with 60-100% of lesions found in the FT fimbria. In addition, pre-invasive STICs, which are defined as in situ cancers with p53 mutations and increased proliferative capacity, are observed in at least 60% of women with HGSC of the ovary and/or peritoneum and similar in situ lesions are not observed in the OSE.
Clinical observations support the hypothesis that STICs can originate from secretory epithelial cells of the fallopian tube (FTSECs) and progress to HGSC by rapidly disseminating to involve ovarian and peritoneal surfaces. However, these associations are largely circumstantial and necessitate experimental proof in order to confirm the role of FTSECs and STICs in serous carcinogenesis. The vast implications of unequivocally establishing a potential cell of origin in HGSC for both cancer prevention and early tumor detection prompted us to develop animal models that mimic human pathogenesis. To this end we targeted defined genetic human alterations, such as BRCA1, BRCA2, and P53, within mouse fallopian tubal secretory cells (FTSECs) in order to recapitulate the steps of fallopian tube transformation into ovarian cancer, thereby providing the first experimental evidence for a FTSEC origin of HGSC in BRCA carriers. In order to generate a clinically informative mouse model of HGSC, we targeted the FTSEC using specific lineage markers, which are expressed in normal FTSEC and in nearly all HGSC cases but not in the ovary or OSE. In this study, we describe the first mouse model for de novo high-grade serous carcinoma originating in the clinically relevant site of the fallopian tubal epithelium. This model accurately recapitulates the clinical features of the human disease and establishes that the FTSEC and STIC can be a cell-of-origin and precursor lesion for HGSC, respectively. This model further confirms the transformation continuum from STIC to HGSC and mimics the underlying molecular alterations, along with the histological, immunophenotypic, increased CA125 levels, and genomic patterns that have been associated with human high-grade serous carcinomas.
These findings offer a new avenue to address clinically important questions that are critical for cancer prevention and early detection in women carrying BRCA1 or BRCA2 mutations. Since our models closely mirror the human disease, they will be of great use to answer many key questions in HGSC pathogenesis. First, it will be possible to establish specific time points at which pre-invasive lesions become invasive in order to shed light on early stage versus metastatic disease. Secondly, these murine models can also be effectively exploited to study FT transformation, and because we have been able to differentiate between secretory and ciliated cells, our model provides the ability to study the role of hormones, ovulation, and follicular fluid in ovarian carcinogenesis.
Early detection of HGSC is difficult but the concept is highly attractive because it can conceivably be achieved at less cost and burden to the patient. If a significant proportion of “ovarian” cancers actually emerge from the distal fallopian tube, a significant shift in both conceptual thinking and preventive strategy will be required. One of the most actively debated questions based on this new model of pathogenesis is whether patients at high-risk for high-grade serous ovarian carcinoma should have only the affected distal portion of the fallopian tube removed, rather than both tubes and ovaries. Can these young BRCA women be offered risk-reduction surgery without undergoing surgical menopause and loss of their fertility? Thus, the first goal of our research has been to produce a valid model for BRCA serous high-grade tumors. The second is to identify unique characteristics of early serous carcinogenesis in the tube that can be exploited for early detection and to examine the causes of the earliest events preceding malignancy, which will create a great opportunity for cancer prevention in high-risk women. It is clear that events leading to the development of STICs play a significant role for the development of serous tumors and resolving their pathogenesis will enable more efficient methods for early detection, tumor imaging, cancer prevention, and identification of populations at risk.
This abstract is also presented as Poster B4.
Citation Format: Gregory A Wyant, Ruth Perets, Katherine Muto, Barish B. Poole, Jin YH Chen, Anders W Ohman, Sunita R Setlur, Christopher P. Crum, Ronny Drapkin, Daniela M. Dinulescu. Transformation of the fallopian tube secretory epithelium leads to high-grade serous ovarian cancer in BRCA/P53 models. [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 PR01.