Genome instability is associated with virtually all cancer types, but the underlying gene defects and mutations causing genome instability are not well understood. Mutations that cause chromosome instability (CIN), or abnormal chromosome numbers, are now widely recognized as predisposing factors that drive cancer formation. In fact, mutations in CIN genes are associated with disease progression, the acquisition of drug resistance and poor patient survival. Nevertheless, and despite these associations, the mutated genes giving rise to CIN remain largely unknown. Thus, a fundamental goal of our research team is to identify and characterize new CIN genes, and to uncover their roles in cancer development. To achieve this goal, we routinely couple genetics, biochemistry, cell biology, molecular biology and high-content imaging microscopy to identify the mutated genes and abnormal pathways that drive colorectal and ovarian cancer formation.
The second major goal of our research team is to identify and develop novel therapeutic strategies to combat cancers, like colorectal, ovarian and breast. In this regard, we use genetics, cell biology and innovative microscopy approaches to screen and identify new drug targets and lead chemotherapeutics that specifically kill cancer cells with mutated CIN genes. A major benefit of this approach is that the therapeutic effects are better targeted towards cancer cells, and thus it is predicted to minimize and/or eliminate the adverse side effects associated with many current chemotherapeutics. This innovative cancer-specific targeting concept is referred to as synthetic lethality and is now beginning to show promise within the clinic.
One area of research in my laboratory is the study of programmed cell death or apoptosis, a form of cell suicide. As a result of genetic changes, cancer cells have a reduced or slowed ability to undergo apoptosis, which can also make tumour cells more resistant to anti-cancer drug treatment. To better understand programmed cell death, we have taken a genetic approach. Several mutant cell lines have been isolated that are defective in apoptosis. This was done by using a specially constructed virus that, after it infects a cell, integrates into genes and interferes with their function. After selection for drug resistant cells, the underlying genes disrupted by the virus are studied for their role in programmed cell death and drug resistance. By understanding the genetic basis of resistance to cell death, completely new treatments can be devised.
A gene that came out of these screens was the Dlc-2 (Deleted in liver cancer two) tumour suppressor gene. We are now studying the role this gene plays, along with the closely related Dlc-1 gene, in tumour cell progression and drug response. The Dlc-1 gene is found deleted in over 50 percent of breast, lung, liver and colon cancers. Also, the other normal copy of the gene is frequently silenced by promoter methylation. To study the role these genes play in the body, we have developed conditional knockout mouse models. With these mouse models, we can study the role the Dlc genes play in lung, and breast cancer spread through the body and anti-cancer drug response.
5022-675 McDermot Ave
Winnipeg, Mb R3E 0V9
Email: Dr Michael Mowat PhD
Human epithelial ovarian cancer (EOC) is the fifth leading cause of death by cancer amongst women. Approximately 95 women in Manitoba will be diagnosed with EOC this year. If detected at early stages of the disease, the cure rate approaches 90%; however, >70% of women are diagnosed with advanced disease when rates of survival are closer to 30%. Even after initial successful responses to therapy, EOC recurs in ~85% of patients. My laboratory uses a combination of cellular and molecular approaches to investigate human EOC biology with a special interest in recurrent, chemotherapy-resistant disease. With the formation of the Manitoba Ovarian Biobanking Program (MOBP) and cooperation with national programs such as the Canadian Ovarian Cancer Research Consortium (COCRC), his lab will be able to more readily translate data obtained with EOC patient samples to clinically relevant results. The ability to isolate and use patient donated EOC cells in 3-dimensional primary culture provides a more relevant model to assess cell responses. In particular, he and his staff and trainees, in collaboration with other University of Manitoba scientists in RIOH and the Regenerative Medicine Program, are focusing on investigating aspects of EOC cell biology and chromosomal instability, in addition to evaluating novel lipid-based therapeutics for treatment of chemoresistant EOC. This laboratory-based research is being complemented by epidemiologic studies with colleagues in Gynecologic Oncology and the Department of Epidemiology at CCMB to evaluate whether recent changes in clinical management have produced positive outcomes for the EOC population in Manitoba.
Rm 333 Basic Medical Sciences Bldg.
745 Bannatyne Avenue
Canada R3E 0J9
Tel. (204) 789 3708 (office)
Tel. (204 272 3174 (laboratory)
Fax (204) 789 3900
Email: Dr Mark Nachtigal PhD