Evaluating the role of metalloproteinases in cancer cell biology: a structure-function approach

Previous and current research
We are studying the extracellular metalloproteinases (MPs) of the matrix metalloproteinase (MMP) and disintegrin metalloproteinase (ADAM) families. These enzymes are key players in the regulation of the cellular environment, are made by all cell types involved in tumourigenesis and are critical to tumour development. Previously we focussed on soluble members of the MMP family and their role in the turnover of the extracellular matrix. We addressed the relationships between MMP domain structure and function, developing valuable tools for the research.

We are also interested in the natural inhibitors of MPs, the TIMPs, and the structural basis for their MP specificity profiles were elucidated using protein engineering techniques. More recently we have considered the further roles of the MPs in the modulation of other components of the microenvironment, including cell adhesion molecules, growth factors and receptors.

Currently we are studying membrane associated MMPs, notably MT1 MMP and its cellular regulation. This enzyme is key to cell migration and proliferation within the collagen and fibrin environments common in many carcinomas. The development of 3D mini tumour models has allowed us to consider MT1 MMP function in both the stromal fibroblast component and in angiogenesis. The role and regulation of some of the proteolytic ADAMs is also being addressed in both 2D and 3D cell models.

Future projects
Based on our knowledge of the structure-function relationships of MPs and TIMPs we are developing specific tools which will allow firther interrogation of the role of these proteins in cell biology and may act as paradigms for the development of future therapeutic agents. Engineered versions of the TIMPs and specific fragment antibodies to MPs will be prepared and assessed.