Translational application of well-supported, fundamental ovarian cancer research to potential improved clinical outcome for ovarian cancer patients cannot be emphasized enough. Every year in Canada alone, about 2400 women will be diagnosed with ovarian cancer and 1700 women will die of this disease (2009 Canadian Cancer Statistics). This is entirely due to the lack of reliable early detection methods combined with poor therapeutic management of recurrent disease. Taken together, my proposed research program will further elucidate the functional implications of altered bone morphogenetic protein (BMP) signalling in epithelial ovarian cancer (EOC) cell adhesion and metastasis and ID proto-oncogene expression in ovarian cancer initiation and progression. I will also utilize important, current techniques which are critically relevant to ovarian cancer research, including culturing and characterization of primary human ovarian surface epithelial (OSE) and EOC cells, three-dimensional multicellular EOC spheroids, as well as the more recently-established transgenic mouse models of this disease. I foresee the direct translational potential of my proposed research via the rapid initiation of key collaborative research efforts with basic and clinical scientists of the Translational Ovarian Cancer Research Group of the London Regional Cancer Program and the University of Western Ontario.
1. Implications of activated BMP signalling and Id1/Id3 function in ovarian cancer pathogenesis
2. Development of novel transgenic mouse models to test the fallopian tube origin of high-grade serous ovarian cancer
3. Three-dimensional primary human EOC spheroids as an in vitro model to study metastasis
4. Establishment of the chick chorioallantoic membrane (CAM) as an in vivo model of EOC metatstasis
5. Investigating the therapeutic potential of Myxoma virus-mediated oncolysis in ovarian cancer 6. The wound healing mediators hyaluronic acid-CD44-RHAMM axis as potential biomarker for early detection of ovarian cancer
• Trevor G. Shepherd, Michelle L. Mujoomdar and Mark W. Nachtigal. (2010) Constitutive activation of BMP signalling abrogates experimental metastasis of OVCA429 cells via reduced cell adhesion. Journal of Ovarian Research 3: 5.
• Natasza A. Kurpios, Lesley MacNeil, Trevor G. Shepherd, David G. Gludish, Andrew O. Giacomelli and John A. Hassell (2009) The Pea3 Ets transcription factor regulates differentiation of multipotent progenitor cells during mammary gland development. Developmental Biology 325:106-21.
• Shepherd, Trevor G., Theriault, Brigitte L., and Nachtigal, Mark W. (2008) Autocrine BMP4 signalling regulates ID3 proto-oncogene expression in human ovarian cancer cells. Gene 414: 95-105.
• Theriault, Brigitte L., Shepherd, Trevor G., Mujoomdar, Michelle L. and Nachtigal, Mark W. (2007) BMP4 signalling induces EMT and promotes the aggressive phenotype of human ovarian cancer cells. Carcinogenesis , in press.
• Shepherd, Trevor G., Theriault, Brigitte L., Campbell, Elizabeth and Nachtigal, Mark W. (2006) Primary culture of ovarian surface epithelial cells and ascites-derived ovarian cancer cells from patients. Nat Protocols 1: 2643-2649. • Fu, Yangxin, O'Connor, Laura M., Shepherd, Trevor G., Nachtigal, Mark W. (2003) The p38 MAPK inhibitor, PD169316, inhibits transforming growth factor B (TGFB) induced Smad signaling in human ovarian cancer cells. Biochem Biophys Res Commun , 310: 391-397.
• Shepherd, Trevor G., and Nachtigal, Mark W. (2003) Identification of a putative autocrine bone morphogenetic protein (BMP) signaling pathway in human ovarian surface epithelium (OSE) and ovarian cancer (OC) cells. Endocrinology 144: 3306-3314.
• Shepherd, Trevor G., Kockeritz, Lisa, Szrajber, Michelle R., Muller, William J. and Hassell, John A. (2001) The pea3 subfamily ets genes are required for HER2/Neu-mediated mammary oncogenesis. Curr Biol 11: 1739-1748.