Vanderhyden Lab

Members of the Ovarian Cancer Research Program, August 2007

There are a number of research projects currently active in the Vanderhyden lab, and a brief description of each is provided below.

Mouse Models of Ovarian Cancer
Animal models that spontaneously develop cancer can help us understand the process of tumour formation and can aid in the investigation of novel prevention and treatment strategies. Recently, we have developed several mouse models of ovarian cancer to assist in our understanding of this disease. Our first model, developed through collaboration with scientists at the Fox Chase Cancer Center, is a transgenic model in which mice predictably develop epithelial ovarian cancer. While these mice develop ovarian cancer at an early age, they are useful for the testing of potential therapeutics, including novel oncolytic viruses. Subsequently, we have developed two additional mouse models of ovarian cancer which allow us to control the timing of disease initiation. These models are based on the Cre-lox system and the conditional activation of oncogenes or inactivation of tumour suppressors following the intra-bursal injection of adenoviral vectors expressing cre recombinase. These models are proving to be useful for the study of early lesions of disease and the response of disease initiation and progression to changes in the hormonal status of the model animals.

Effects of reproductive and genetic factors on ovarian cancer initiation and progression
The majority of ovarian cancers arise from the surface cells of the ovary, but the cellular and molecular events associated with early development of ovarian cancer are poorly understood. Epidemiologic evidence has identified a variety of reproductive factors that increase the risk of ovarian cancer, such as ovulation and certain hormones, notably estrogen. In addition, aging and hereditary risk (family history) are associated with the more frequent incidence of pre-cancerous structures in the ovary. The mechanisms by which these factors enhance the risk of ovarian cancer are unknown. The goal of this project is to address how ovarian cancers begin, with particular emphasis on reproductive and genetic factors that have been implicated in the initiation or progression of ovarian cancer, especially estrogen and a family history of the disease due to inheritance of BRCA1 mutations. We are examining the characteristics of the ovarian surface cells, determining how these cells transition to become cancer cells, and investigating how reproductive and genetic factors, such as estrogen, menopause and BRCA1 mutation, may promote the development of ovarian cancer by manipulating the behaviour of these surface epithelial cells.

Early events in ovarian tumourigenesis and the role of HOX genes in the development of distinct histologic subtypes of ovarian cancer
High-grade epithelial ovarian cancer (EOC) is thought to arise from the ovarian surface epithelium (OSE). Unlike other epithelial cancers, neoplastic progression of EOC is associated with increasing commitment to the epithelial phenotype, with enhanced formation of papillae and glandular structures reflected in distinct histologic subtypes. The genes responsible for epithelial differentiation of OSE and their contribution to tumourigenesis are unknown, although the HOX transcription factors have recently been implicated in this process. In this study, we are using our most recent mouse model of ovarian cancer which has conditional expression of the SV40 early region (T Antigen). The female mice reliably develop EOC following intrabursal administration of adenovirus expressing Cre recombinase, which provides us with the rare opportunity to examine the early events of ovarian tumourigenesis. We are using this model to define the cellular and molecular events that contribute to early ovarian tumourigenesis and to improve the model to recapitulate the various histologic subtypes of ovarian cancer. Because the mice develop cancers in situ in a manner that strongly resembles human ovarian cancer, we anticipate that they will be validated as clinically-relevant models for the pre-clinical evaluation of therapeutics.

Chromatin remodelling proteins involved in cellular differentiation
The switch from a proliferative to a differentiated state requires a cell to undergo sweeping changes in gene expression that is dependent on global chromatin remodelling within the nucleus. ISWI or SWI2/SNF2 proteins constitute the catalytic subunit of chromatin remodelling complexes that alter nucleosome positioning to regulate gene expression. We are collaborating with Dr. David Picketts to investigate the expression and function of Snf2h and Snf2l, chromatin remodelling proteins that seem to play a role in regulating cellular proliferation vs differentiation. As normal differentiation of granulosa cells is essential for female fertility, this project aims to examine the expression and function of the Snf2h and Snf2l genes during follicle development and corpus luteum formation, and to develop an animal model of infertility by disrupting the normal differentiation process in granulosa cells. We are also investigating the function of these proteins in ovarian cancer cells.

The Kit tyrosine kinase receptor and ovarian cancer
Growth factor/receptor autocrine loops are important features of some cancers. We have found that the c-kit protooncogene, which encodes the Kit tyrosine kinase receptor, is expressed in ovarian tumour cells, but not in normal ovarian surface epithelial cells, the cellular source of most ovarian cancers. Using cultures of normal human, rat and mouse surface epithelial cells and ovarian cancer cell lines, we are investigating epithelial-stromal cell interactions, epithelial-extracellular matrix interactions, and the role of Kit signalling in ovarian tumour induction, progression and chemosensitivity. Ovarian tumours are being screened to assess the diagnostic and prognostic value of Kit expression. As a consequence of these in vitro studies, we recently completed a U.S. Gynecologic Oncology Group clinical trial administering the Kit inhibitor Gleevec to ovarian cancer patients.

Function of the c-Kit protooncogene in the ovary
The c-Kit protooncogene encodes a tyrosine kinase receptor present in germ cells. Aberrant expression of this receptor or its ligand results in defective gonadal development. We are investigating the function of this ligand-receptor interaction in the developing ovary. The Kit receptor is expressed in oocytes throughout development and its ligand, kit ligand (KitL), is produced by the surrounding somatic (granulosa) cells, suggesting that activation of the Kit receptor on oocytes may regulate growth, survival and/or cell cycle (meiosis). Using cellular and molecular techniques, hormonal and growth factors that regulate KitL expression in granulosa cells during follicle development are being examined. Regulation of Kit activation and subsequent signal transduction events are being investigated using oocyte culture systems and ovaries from mice bearing mutations that result in impaired oocyte development.

Regulation of ovarian granulosa cell function by germ cell-derived factors
The ovary is an ideal organ to study the regulatory mechanisms involved in cellular differentiation, proliferation and apoptosis because it is continuously undergoing these processes in a predictable manner. Research in this lab examines the function of somatic cell-germ cell interactions in the development of the ovarian follicle. Using tissue culture and micromanipulation techniques, the role of the oocyte in the regulation of granulosa cell differentiation, proliferation and steroid hormone production are being investigated. Some of the oocyte activity can be attributed to the oocyte-specific growth/differentiation factor-9 (GDF-9), so we are using GDF-9 knockout mice to determine the mechanisms by which oocyte-secreted factors like GDF-9 affect granulosa cell function.

Please explore the page on lab members for more information about the lab members and their research projects.