Sashko DamjanovskiWestern Science

Research

My lab has traditionally used frog development as a model to study cell movement in the context of extracellular matrix (ECM) remodelling. The ECM is a mixture of secreted proteins that “glue” cells together in tissues. Thus, for cells to move the ECM must be altered. Secreted enzymes (matrix metalloproteinases – MMPs) facilitate such remodelling by degrading the ECM. Such MMP activity and cell migration is prevalent during embryogenesis, but largely absent in adults, except in cases of tissue remodelling associated with injury and in disease, such as during cancer metastasis. As MMPs play many crucial roles in embryogenesis, we have published many papers on the roles of MMPs in frog embryos. We described that specific secreted molecules (TIMPs) need to act together with MMPs. Thus it is not the absolute level of an MMP nor its enzymatic activity that is meaningful, but MMPs and TIMPs working collectively. They regulate cell signalling and cytoskeletal rearrangement events, which are as important to migration as the remodelling of the ECM. Towards further investigating ECM remodelling we recently used in vitro cell culture and live imaging using MCF-7 breast cancer cells to demonstrated that it was not the absolute level of MMP enzymatic activity that was related to cell migration. This involved the use of novel 3D cell culture techniques together with a variety of florescent labels and substrates that allowed the real time visualization of MMP activity and cell movement. It is moderate levels of MMP-14 that manifests in increased cell pERK signalling and changes in cell shape that aid cell migration, not high levels of MMP activity.