Vanderhyden Lab

Ken Garson, Ph.D., Research Associate

One important research direction that will advance our understanding of ovarian cancer and generate tools for the pre-clinical evaluation of new therapeutics is the development of transgenic mouse models of ovarian cancer. The first major challenge to developing these models was the targeting of oncogene expression to the ovarian surface epithelium, the layer of cells which gives rise to epithelial ovarian cancer. Our first two mouse models of epithelial ovarian cancer have met this challenge by directing oncogene (SV40 T antigen) expression directly to the ovary using either the MISIIR promoter (tgMISIIRTAg model) or by exploiting the cre/loxP recombination system to activate the expression of this same oncogene in the ovarian surface epithelium. In this latter model (tgCAG-LS-TAg model), conditional activation of the SV40 T antigen is achieved by the injection of AdCre (an adenovirus expressing cre recombinase) into the bursal space surrounding the ovary. Interestingly, the tgMISIIRTAg model offers “two models for the price of one” since the female mice reproducibly develop bilateral epithelial tumours of the ovary (with occasional peritoneal ascites and metastases) and the male mice develop tumours of the prostate. The tgMISIIRTAg female mice are well suited for the testing of novel therapeutics (see Valerie Snoulten) since they develop ovarian tumours with very reproducible kinetics. One disadvantage of this model is the appearance of nascent tumours in very young mice. The control and delay of tumourigenesis has been achieved in the tgCAG-LS-TAg model by the timed injection of AdCre. This permits the study of early disease and parameters that affect it (See Laura Laviolette). In addition to the continued characterization and exploitation of the above models, we have started to develop reagents for our next generation of models. The two major goals for our future models are to directly express or suppress genes with established roles in ovarian carcinogenesis and to modulate the differentiation of tumours into the different histological subtypes observed in the clinic.

Elizabeth MacDonald, M.Sc., Research Technician

I am a research technician and have been working in Dr. Vanderhyden's lab for 13 years. I am responsible for maintaining the transgenic mouse colonies, working in a pathogen-free barrier facility where I carry out breeding, identification and genotyping of pups by PCR. I am also involved in the analysis of nascent ovarian tumours developed in the tgCALL-TAg mouse model through the use of Real Time PCR and Laser Capture Microscopy technologies.

Olga Collins, B.Sc., Research Technician

I am a research technician in Dr. Vanderhyden's lab. I form part of the mouse models of ovarian cancer group in our lab. My work focuses on the isolation, growth, and characterization of mouse ovarian surface epithelial cells and how they transform into ovarian cancer. With Lisa Turchet, I am also exploring the possible existence of a progenitor cell population within the ovarian surface epithelium.

Colleen Crane, Medical Laboratory Technologist

My priority in the Vanderhyden lab is to maintain the tissues and corresponding records for the Ottawa Ovarian Tumour Bank. I was a major contributor to the translational research component of the Gynecologic Oncology Group clinical trial of Gleevec in ovarian cancer patients, performing and analyzing all related immunostaining. My training as a cytologist is put to good use as I am the official tissue embedder and sectioner in the lab, participating in nearly all projects in the group, especially the development and characterization of mouse models.

Jin-Yi Jiang , Ph.D., Post-Doctoral Fellow

I am interested in the cellular and molecular mechanisms in the regulation of ovarian follicular development and atresia, and oocyte growth and maturation. My current studies are focusing on 1) the importance of Kit ligand (KitL), a granulosa cell-derived factor, in the promotion of oocyte growth, and 2) the regulation of KitL expression by intraovarian factors (i.e. TGF-beta).

David Pepin, Ph.D. Candidate

If every cell in my body has the same DNA, how does a neuron remember it is a neuron and not a muscle cell? The original stem cell that gives rise to a human being must be able to specialize into many different cell types. Yet during development, the genetic content does not change. There must therefore be another source of information beyond genetics. This epigenetic information is stable and makes sure a neuron expresses only neuron genes. The average cell faces a double challenge: it must be able to pack a 2m worth of DNA into a nucleus whose diameter is only one-millionth of a meter across, and still be able to read the genes it needs. Evolution has found a way to tackle both these problems at once by making the packaging itself the carrier of this information. DNA is tightly wound-up around spools of histones to save space. Those histones can carry stable chemical marks such as methylation and acetylation. This has lead to the histone code hypothesis, which stipulates that those very modifications make-up a language that regulates which genes must remain accessible to be read and which can be compacted. While the histone code has yet to be cracked, the purpose of my research is to study how a gene called ISWI reads and integrates some of this code. Understanding how this happens has far-reaching consequences: from programming stem cells to become the cell of our choosing to stopping cancer cells, which are really just cells that have forgotten their identity and behave more like stem cells. Supported by an Ontario Graduate Scholarship in Science and Technology.

Laura Laviolette, Ph.D. Candidate

Examining the role of the reproductive hormones on ovarian cancer initiation and progression.
My PhD thesis project involves examining the role of the female reproductive hormones (LH, FSH, estrogen and progesterone) on ovarian cancer initiation and progression. I work with a transgenic mouse model of ovarian cancer (tgCAG-LS-TAg) developed to mimic the genetic and physiological characteristics of human ovarian cancer. I use this mouse model to study the effects of prolonged exposure to exogenous hormones (similar to women using oral contraceptives and hormone replacement therapy which are combinations of estrogens and progestins) and menopause (high gonadotropins and low steroid hormones) on ovarian tumourigenesis. My research will lead to a better understanding of the epidemiological evidence, which suggests that oral contraceptive use is protective against ovarian cancer, whereas hormone replacement therapy and menopause are associated with an increased risk of developing the disease. Supported by a Ontario Women’s Health Council/CIHR - Institute of Gender and Health Doctoral Research Award.

Lisa Turchet, Ph.D. Candidate

Identifying and characterizing potential adult stem cells on the surface of the ovary.
I obtained a Bachelor of Science, Honours degree in Biochemistry and Physiology at the University of Ottawa, and am now working on a Ph.D. that addresses how normal ovarian cells may become cancer cells. Almost 90% of ovarian tumours are thought to arise from the ovarian surface epithelium (OSE), a layer of cells that covers the surface of the ovary and is ruptured during ovulation. The remaining OSE cells proliferate rapidly to regenerate the surface layer of cells. Rapid healing also occurs in other epithelial tissues (intestinal epithelium) where stem cells are the source of proliferating cells. We believe that the OSE contains stem/progenitor cells that provide the rapidly proliferating cells that close ovulatory wounds. A higher number of ovulations during a women’s lifetime is linked to a higher risk of developing ovarian cancer and stem cells by definition may be the only cells present in the OSE long enough to acquire the mutations thought to lead to tumour formation. Therefore incessant ovulation may cause OSE stem cells to become dysregulated and give rise to cancer cells. I am working to identify stem cells in the OSE and to characterize their role in ovulatory wound healing and in the early stages of ovarian cancer. Supported by a Canadian Institute of Health Research Canadian Graduate Student Master’s Award.

Valerie Snoulten, M.Sc. Candidate

Testing the therapeutic efficacy of an oncolytic virus on a mouse model of ovarian cancer.
Oncolytic viruses are potential novel therapeutics to aid in the treatment of cancers. These are viruses that have either been naturally selected or engineered to selectively grow in and kill tumour cells without harming normal cells. VSV is an oncolytic virus that has been shown to be effective in vitro and in vivo in xenograft and syngeneic mouse models of cancer. Many mouse models of cancer that have been treated with VSV have shown an increase in the survival and/or a decrease in the tumour burden of the mice. Our lab has generated a line of transgenic mice (tgMISIIRTAg ) in which 100% of the females develop bilateral ovarian tumours. My project focuses on the treatment of these mice with VSV in order to determine its efficacy in the treatment of ovarian cancer. Supported by an Ontario Graduate Scholarship in Science and Technology.

Elizabeth Pitre, M.Sc. Candidate

Identifying the role of the developmental HOX genes in the differentiation of epithelial ovarian cancer.
I obtained my undergraduate degree, an Honours B.Sc. in Bio-Medical Science, from the University of Guelph. I joined the Vanderhyden lab to investigate the role of HOX genes in the progression of epithelial ovarian cancer. HOX genes play a critical role in the patterning and development of the female reproductive tract, and they are also abnormally expressed in the histologically distinct subtypes of epithelial ovarian cancer. My research project involves using in vitro culture models and a mouse model of ovarian cancer to determine the effects of HOX genes on the differentiation of this malignancy into its various subtypes. Supported by an Ontario Graduate Scholarship.

Behnam Azadi , M.Sc. Candidate

Investigation of synergistic effect of soy milk components and fenretinide on ovarian cancer cells.
The use of herbal or natural products is growing significantly worldwide. These products can interact with synthetic drugs, but the particular interactions between natural anti-cancer drugs derived from soy milk and fenretinide against ovarian cancer have not yet been tested. Fenretinide is a synthetic retinoid derived from vitamin A that is currently undergoing testing as a chemopreventive and chemotherapeutic agent and is therefore a promising agent for ovarian cancer therapy in the near future. Evidence from recent studies demonstrate that bioactive compounds from soy milk in physiologic concentrations can kill cancer cells. My M.Sc. thesis project involves understanding the interaction between natural drugs from soy milk and fenretinide. The goal of my project is to optimize the combination of natural and synthetic drug to cause the strongest effects on the cancer cells. Identification of any synergistic effects may reduce the dose of fenretinide needed to achieve maximum effect and consequently minimize its side effects. In my research project I am using an in vitro cell culture models and will evaluate the cytotoxicity of drugs on ovarian cancer cell lines. I obtained a B.Sc. degree in biomedical sciences from Iran Azad University.