Senior Scientist, Cancer Therapeutics, Ottawa Hospital Research Institute
Corinne Boyer Chair in Ovarian Cancer Research, University of Ottawa (www.med.uottawa.ca/vanderhyden/)
Professor, Cellular & Molecular Medicine, and Obstetrics & Gynecology, University of Ottawa
Major Research Programs
Mouse Models of Ovarian Cancer: Animal models that spontaneously develop cancer enable us to understand the process of tumour formation and aid the investigation of novel prevention and treatment strategies. Currently, there are few mammalian models of ovarian cancer, which greatly hinders the ability to test novel therapeutics in a physiologically relevant manner. We are using the first transgenic mouse model of ovarian cancer to investigate the early events associated with tumour initiation, the impact of BRCA1 and hormones on disease progression, and the testing of novel therapeutics, including oncolytic viruses. Additional aims of this project are to determine genetic alterations that are oncogenic in surface epithelium and to generate models of ovarian cancer using a variety of strategies, including cell-specific expression of oncogenic signals, the Cre-lox system for conditional expression, and intra-bursal injection of adenoviral vectors.
Paracrine factors controlling oocyte growth and developmental competence: Ovarian folliculogenesis is dependent upon somatic cell-germ cell interactions mediated by paracrine factors and gap junctions. Loss of expression of Kit or its ligand (Kitl) results in defective gonadal development, demonstrating the importance of KIT activity for ovarian function. We are investigating the role of hormonal (FSH) and paracrine factors (BMP-15, GDF-9) in follicular development, with emphasis on how these factors affect the KITL-KIT interactions that are critical for oocyte growth. Regulation of KITL expression, KIT activation and subsequent signal transduction events are being investigated using follicle culture systems, micromanipulation, and ovaries from mice bearing mutations that result in impaired oocyte development and infertility.
Chromatin remodelling proteins involved in cellular differentiation
The switch from a proliferative to a differentiated state requires changes in gene expression that are dependent on 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 investigating the expression and function of Snf2h and Snf2l, chromatin remodelling proteins that seem to play a role in regulating cellular proliferation vs. differentiation in reproductive tissues. As normal differentiation of granulosa cells is essential for female fertility, this project aims to determine the role of Snf2h and Snf2l in 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 testicular function and ovarian cancer cells.
Selected Publications
Garson K, TJ Shaw, KV Clark, DS Yao and BC Vanderhyden (2005). Models of ovarian cancer-Are we there yet? Mol. Cell. Endocrinol. 239: 15-26.
Lazzaro MA, D Pépin, N Pescador, BD Murphy, BC Vanderhyden and DJ Picketts (2006). The ISWI protein SNF2L regulates steroidogenic acute regulatory protein (StAR) expression during terminal differentiation of ovarian granulosa cells. Mol. Endocrinol. 20: 2406-2417.
Clark-Knowles KV, K Garson, J Jonkers and BC Vanderhyden (2007). Conditional inactivation of Brca1 in the mouse ovarian surface epithelium results in an increase in preneoplastic changes. Exp. Cell Res. 313: 133-145.
Shaw TJ and BC Vanderhyden (2007). AKT mediates the pro-survival effects of KIT in ovarian cancer cells and is a determinant of sensitivity to imatinib mesylate. Gynecol Oncol. 105:122-131.
Thomas FH, RS Ismail J-Y Jiang and BC Vanderhyden (2008). Kit ligand 2 promotes murine oocyte growth in vitro. Biol. Reprod. 78: 167-175.
Shaw TJ, EC Lacasse, JP Durkin and BC Vanderhyden (2008). Down-regulation of XIAP expression in ovarian cancer cells induces apoptosis in vitro and in vivo. Int. J. Cancer 122: 1430-1434.
Schilder RJ, MW Sill, RB Lee, TJ Shaw, MK Senterman, AJP Klein-Szanto, Z Miner and BC Vanderhyden (2008). A Phase II evaluation of imatinib methylate in the treatment of recurrent or persistent ovarian or primary peritoneal carcinoma. J. Clin. Onc. 26: 3418-3425.
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