Engrailed 2 regulation of prostate cancer metastasis
Jules JE Doré, Ph.D., Memorial University of Newfoundland, Faculty of Medicine
I am Dr. Jules Dore, born in Calgary, Alberta but grew up in a small farming community south of Vancouver, British Columbia. I gradated from the University of British Columbia, with first class honours B.Sc. in Zoology and continued my education earning a MS degree from the University of Florida and a PhD from the University of Tennessee. Between my two graduate degrees I worked for a venture capital biotech startup company in Vancouver, QuadraLogic Technologies. It is this experience that has given me a unique understanding of both academia and commercialization of biotechnology. After my PhD, I did a Post-Doctoral fellowship at the Mayo Clinic in Rochester, Minnesota, in the Thoracic Disease Research Unit. It was from there that I started my faculty appointment at Memorial University in 2002, in the Faculty of Medicine. In 2012 I took up my present appointment as the Assistant Dean of Graduate Studies in the Faculty of Medicine. My research program has focused on the fundamental nature of how cells growth is controlled, using Transforming Growth Factor-beta as a model since it is able to both stimulate or inhibit growth of cells, dependent on what type of cells it is given too. I have approximately 20 peer-reviewed manuscripts in this area of basic research, with 34 in total. Most cancers originate from epithelial cells, the cell type that is normally inhibited by Transforming growth factor-beta. Most epithelial cancers have lost this necessary “brake system” resulting in their uncontrolled, rapid growth. A number of years ago I joined with Dr. Kao, a member of the Terry Fox Cancer Research Labs and Dr. John Thoms, a Prostate Oncologist with Eastern Health, to help build a team of highly motivated investigators and pool our expertise in order to make significant progress in the fight to cure prostate cancer.
The most pressing clinical challenge facing prostate cancer patients is that their disease evolves over time into a a type called Neuroendocrine. This type of prostate cancer does not respond to drug therapies and spreads very quickly, making it highly lethal. Our group has identified that these cancers express a neurodevelopmental gene, Engrailed2, not in early tumours but only during the time that the cancer is evolving into the Neuroendocrine type. From our previous research we have found that Engrailed2 increases prostate cancer cells ability to migrate but has no effect on growth rate. The present project proposal extends this work, presently funded by RFD, to identify exactly how Engrailed2 is changing prostate cancer cells so that they migrate faster. By doing that we can then identify ways of turning this ability off. Thus our intent to find ways to stop prostate cancer from spreading to other parts of the body. Surgeons can effectively remove tumours if they remain in one place, but once it spreads, options become very limited and death commonly follows.
The progression of prostate cancer from treatable, androgen responsive to metastatic, drug-resistant neuroendocrine-type appears to be an inevitable course of this disease. We have identified a neurodevelopmental gene, Engrailed 2 (EN2), whose expression levels follows this same course. By exogenously expressing EN2 in an early prostate cancer cell line (22Rv1) we found that it alters this normally non-migratory cell line into a migratory one. Understanding the mechanism by which EN2 does this is the focus of this proposal. We intend to address this by validating a list of genes associated with motility and transformation obtained from our present work. Second our intent is to knockout the expression of EN2 in a prostate cancer cell line that expresses it (PC3) and determine the subsequent changes in the expression of these same genes and the effect on migration/invasion. Third, extending our recent finding that a miRNA under the regulation of transforming growth factor-beta causes the degradation of EN2 mRNA, thus the amount of the protein, to examine this miRNA’s levels in prostate cancer cell lines and determine if it can be upregulated, thus creating a functional knockdown of EN2. Our ultimate goal is to understand how EN2 is changing prostate cancer cells and identify mechanisms by which we can block its detrimental effects.
Impact on prostate cancer patients:
From the information we gain from this investigation we anticipate the initial impact will be to identify to Clinicians this area as a novel route to potentially control prostate cancer metastasis. To patients with the disease, we can offer information that we are making progress on the final stages of the disease evolution that has shown to be clinically difficult to treat and that with this support we may be able to find drug targets by the time their disease evolves to the Neuroendocrine stage.