Spring, 2011

The Canadian Institutes of Health Research (CIHR) has awarded UBC Dentistry professor Chris Overall and his team funding to study tissue destruction and cancer growth. The Overall Lab has developed new techniques employing gene chips and proteomics to identify thousands of proteins at a time in tissues, giving a comprehensive view of diseases such as cancer and inflammation.

Their methods specifically detect the stubs that remain after proteins are dissolved by enzymes called proteases. These protein stubs enable the researchers to decipher which signalling proteins are turned on or off by the proteases. Cells behave differently when the signals are in the “on” or “off ” position, so if switching by proteases goes wrong, disease can result. The protein stubs can be important tell-tale signs, called biomarkers, that could aid in diagnosing disease. This research could lead Overall and his team to home in on targets for the development of new therapeutic drugs to treat cancer and inflammation.

Dr. Chris Overall Secures Funding to Research Breast Cancer Growth

The CIHR has awarded Dr. Chris Overall and co-investigator Dr. Shoukat Dedhar, from UBC’s Department of Biochemistry and Molecular Biology, funding—totalling just over $890,000 over five years—to investigate proteolytic signatures in breast cancer.

Death from cancer mainly occurs when the tumour spreads from its original site to other sites in the body (metastasis). In breast cancer, proteases dissolve the tissue, allowing malignant cells to spread, entering blood vessels and finally going to organs such as the lungs. In cutting signalling proteins, proteases cause the cancer cells to change their behaviour, usually for the worse. Tumours in mouse mammary glands are a good model for human breast cancer.

“We found that highly malignant breast cancer cells make matrix metalloproteinases (MMPs) and other important proteases called ‘matriptases.’ Certain of these proteases are found in primary tumours that metastasize in mice, but are absent from those tumours that do not spread. It is important to know what they do at this stage in helping cancer grow and spread,” Overall explains. “Our gene chips and proteomics techniques can uncover changes in proteins and how they are cut to give proteolytic signatures that occur in breast and lung cancer.” Thus, Overall and his team can decipher the actions of proteases that make tumours more cancerous.

‘Moonlighting Proteins’ Under Investigation—Grant Awarded

Dr. Chris Overall and research associate Dr. Georgina Butler will investigate how proteases change the activity of “moonlighting proteins,”—that is, proteins that have different activities depending on where they are located. Certain proteins that normally function inside the cell can, on occasion, occur outside the cell where some play important signalling roles in inflammation. Overall and Butler’s research, titled “Moonlighting Intracellular Proteins in the Extracellular Matrix,” secured five-year funding—just over $877,000—from the CIHR.

In inflammation, tissue proteins are dissolved by proteases called matrix metalloproteinases (MMPs), which are made by most tissues and white blood cells that fight infection. MMPs destroy tissue by dissolving collagens—rope-like protein structures that add strength to tissues— found in joints and gums, causing loose teeth in gum disease and swollen, sore joints in arthritis. However, MMPs also orchestrate healing and the way white blood cells protect the body from infection by cutting cell signalling proteins. Understanding the moonlighting proteins, how they send signals and how MMPs change those signals is important to fully understand the ways in which inflammation destroys tissues and causes disease.