Cell cytoskeleton, cell adhesion, podosomes, cell migration, chemotaxis

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My research is directed towards understanding the molecular mechanisms regulating directed cell movements and adhesion turnover. Much of the laboratory effort is coordinated with that of some of my colleagues in the Cell Motility & Cytoskeleton Section; Anne Ridley and Maddy Parsons and Dr Claire Wells in the Cancer Division.

Using a combination of optical microscopy techniques including widefield phase contrast/fluorescence time-lapse, LS confocal imaging, FRAP, TIRF, FRET-FLIM and superesolution microscopy, the work of our group examines the dynamics of key proteins involved in forming and breaking up adhesive podosomes and invadopodia in living cells as they migrate over and through selected extracellular matrices.

In collaboration with Professor Adrian Thrasher at the Institute of Child Health we demonstrated that WASP was absolutely required for normal chemotactic movement of both macrophages and Dendritic cells (DC) since in patients lacking WASP, cells fail to respond normally to well-characterised cytokines and chemokines. The failure to show normal chemotaxis is correlated with the absence of podosomes in the macrophages and DC isolated from WAS patients. Furthermore, we demonstrated that both podosomes and normal cell motility could be restored in WAS DC and macrophages  following expression of exogenous WASP constructs. Much of our subsequent work has concentrated on a detailed study of podosome assembly and turnover in normal cells together with examination of partner proteins such a WIP (WASP-Interacting Protein), potential WIP/WASP kinases and the protease calpain that we found to degrade WASP when released from its association with WIP. This work is given extra impetus by the finding that podosomes are also found in many invasive cancer cells. Possible derivatives of podosomes, termed invadopodia, are also seen in many highly invasive carcinoma cell lines, where they act as foci for matrix degradation. We currently have work underway to test the role of these structures in cancer cell invasion into 3-D matrices and the molecular basis for their formation and turnover.