Research Location: BC Cancer Agency - Vancouver

Endothelial cells are a thin layer of cells that line blood and lymph vessels. They play a number of essential and complex roles within the body including acting as a selective barrier to the passage of molecules and cells between the blood and the surrounding bodily tissue. Angiogenesis, the process in which new vessels grow from original vessels, requires endothelial cell growth. Angiogenesis occurs in physiological processes such as wound-healing and menstruation. Malfunctions in angiogenesis – when new blood vessels either grow excessively or insufficiently – can result in serious diseases such as cancer, rheumatoid arthritis, coronary heart disease and stroke. Linda Ya-Ting Chang is studying the mechanism that controls endothelial growth and differentiation – the Notch signalling pathway. By blocking endogenous (originating internally) Notch signaling, she is investigating the response of endothelial cells to stress-induced programmed cell death (apoptosis). Linda is also studying the molecular interactions between the two components of the Notch pathway (the receptors and the ligands) during programmed cell death to determine the important molecular players in the process. The results from Linda’s research will enhance understanding of the process of angiogenesis and may lead to new therapeutic methods for vascular-related diseases.

Under normal circumstances, cells are prevented from dividing uncontrollably by the presence of tumour suppressor genes (TSGs). In order for cancers to grow, these genes must be turned off, either by DNA mutations or by a process called methylation. Methylation turns TSGs off with the introduction of small chemical “tags”, which prompt the cell to fold up the gene and make its DNA blueprint unreadable. This process is reversible, and certain drugs have been shown to remove methyl tags from DNA. Jonathan Davies’ research focuses on developing techniques to identify the TSGs in lung cancer genomes that may be frequently turned off by the methylation process. He hopes to determine the DNA methylation patterns of cells making up lung tumours and identify potential drug targets. If TSGs can be reactivated with de-methylating drugs, it could provide a new treatment option for halting or eliminating the growth of tumours, leading to better care and increased recovery rates for lung cancer patients.

Chronic myeloid leukemia (CML) is a specific type of leukemia in which there is a latent, or dormant, phase for several years before the rapid onset of fatal symptoms. This type of leukemia is difficult to study because the CML cells usually die when they are grown in laboratory conditions. Using human embryonic stem cells for CML research may be a viable option, as this type of cell readily grows in vitro and has the ability to develop into the type of blood cell affected by CML. The cells could be used to mimic some of the genetic changes seen in leukemia to identify important changes that trigger or block the progression of this disease. Melanie Kardel is working to develop techniques for creating leukemic cells from human embryonic stem cells in the laboratory. Because these cells could be grown in the lab for longer periods of time, more extensive studies than are currently possible could be performed, leading to the identification of new targets for therapy. Once targets are identified, this system would also be used to test the potential success of the therapies before they advance to clinical trial.

One challenge with treating solid tumours is ensuring the effective delivery of chemotherapy drugs to all the cells within a tumour. Inefficient penetration of an anti-cancer drug results in insufficient doses reaching cells distant from the tumour’s blood vessels. As a result, these cells may survive and proliferate, allowing the tumour to re-grow. In addition, a low drug exposure may actually contribute to tumour cells developing resistance to a drug. Lynsey Huxham is examining the tumour microenvironment after drug administration and determining which drugs penetrate well. She is focusing on the effects of a drug by examining dividing cells and those undergoing apoptosis (cell death) in relation to their distance from blood vessels. By understanding the process of extra-vascular drug distribution, she hopes to aid efforts to improve the administration and delivery of cancer drugs, as well as offer insight into the design of new chemotherapy drugs.

Follicular lymphoma is a cancer of the lymphocytes (cells of the immune system) and is the most prevalent type of lymphoma in Canada. Most follicular lymphomas are associated with defective cells resulting from the gene regulation process (the process through which the cell determines when and where genes will be activated) resulting in increased production amounts of the protein Bcl-2. This protein prevents lymphocytes from dying at the end of their natural lifespan, causing these altered cells to persist in the body, gain abnormal alterations in their genomes, and eventually develop into cancerous cells. Anca Petrescu is examining how chromosomes in follicular lymphoma are structurally different and rearranged relative to the normal genome, and how these differences may cause cancer. She is studying ten follicular lymphoma genomes and will profile each to discover the rearrangements they harbour. Common rearrangements will be analyzed in detail to determine their exact properties, and their effect on genes. Anca hopes her research will provide insight into the role of recurrent rearrangements in follicular lymphoma, and allow for further research to identify key genes that may be may be of potential diagnostic or therapeutic use.

Research has shown that defects in cilia, small hair-like structures on the outside of cells, are the cause of many disorders including infertility, blindness, deafness, kidney defects and breathing difficulties. It has been shown that some of these defects arise when there are mutations in components of these cilia known as “”Intraflagellar Transport proteins”” (IFTs). These faults may render the cilia immobile, shorter than normal, or even completely absent and can lead to alterations in the normal layout of adult organs such as the heart, liver, and lungs. There are an increasing number of diseases linked with the IFT family of genes. Dr. Robin Dickinson is studying the role of one of them, known as Hippi / IFT57. Robin is investigating what these genes do when active, and examining the effects of their loss. Robin hopes that research into their function will lead to development of therapies for diseases caused by defects in cilia.

Congenital heart defects due to anomalies in heart development occur in one percent of newborns. A critical event during heart development is the transformation of a subset of cells that line the inside of the heart, called endocardial cells, into mesenchymal cells. This process, termed endothelial-to-mesenchymal transition (EMT), generates cells to form heart valves and walls that divides the adult heart into chambers and regulates blood flow. If EMT does not progress properly, normal heart development is disrupted, resulting in the most common type of congenital heart defects. Notch proteins (signaling molecules that trigger genes to activate) play an important role in EMT as the activation of Notch signaling induces the EMT process in endothelial cells. Dr. Yangxin Fu’s research goal is to identify the direct target genes of Notch signaling that are critical to EMT. Using cell culture and molecular biology tools, including a cutting-edge, high throughput technique, Yangxin is analyzing thousands of candidate genes and searching for Notch target genes critical for EMT and heart development. This study will help to understand the molecular mechanism underlying the role of Notch signaling in EMT and in the long term it may find potential target molecules to prevent and treat the heart defects caused by disruption of Notch signaling.

Throughout life, blood cell production is dependent on a rare cell found in the bone marrow called the hematopoietic stem cell. This cell has the unique ability to divide and make identical copies of itself and also to generate progeny cells that can expand and acquire the specialized properties of mature circulating blood cells. Stem cells underpin a wide range of transplantation-based therapies for cancer, leukemia and genetic disorders. The use of these cells for therapeutic purposes requires genetic manipulation of hematopoietic stem cells, which involves inserting gene products directly into the cell’s genome. This procedure can also negatively affect chromosomes flanking the insertion site, causing variations in normal gene expression and malignant growth. Dr. Eric Yung is addressing these issues by developing methods to introduce new genes into stem cells without inserting them directly into the host genome. His strategy is to adapt and modify the ability of certain viruses to insert genetic material into cells. These methods may provide safer and more robust ways to achieve high level expression of genes. They may also aid understanding of the function of specific genes (for example genes that cause cancer) and the development of new methods to expand stem cells and develop new therapies for genetic disorders.