The mechanism of tumour promotion by the Rho-ROCK signalling pathway
We have demonstrated that activating ROCK within the epidermis leads to hyper-proliferation of keratinocytes and promotes tumour formation in a murine squamous cell carcinoma model. This mechanism links ROCK activation and changes to cell tension and tissue stiffness to integrin signalling and the Wnt pathway (Cancer Cell 19(6):776-91). These results strongly support the hypothesis that signalling through ROCK plays a key role in tumour progression.
More recently, we have demonstrated that these mechanotransduction pathways are a relevant feature of human cutaneous SCC (Am. J. Pathol. 183(3):930-7). We are currently working on identifying the mechanism by which the activation of Rho-ROCK signalling within tumour cells promotes tumour progression.
How does the Rho-ROCK pathway generate a permissive tumour microenvironment?
Our laboratory has recently shown that the Rho-ROCK pathway is progressively activated within fibroblasts, macrophages and several other cell types within the tumour microenvironment, during tumour progression. This change is accompanied by increased generation of ECM components, including collagen, fibronectin and periostin, in a ROCK-dependent manner. Taken together, these results strongly suggest that ROCK activation remodels the tissue microenvironment to promote tumour progression. This project seeks to identify the mechanisms by which activation of ROCK generates a tumour-permissive microenvironment, using our conditionally active ROCK mouse models.
How is the Rho-ROCK pathway regulated during wound healing?
Wound healing is much quicker when ROCK is activated in models within which we can control the activation of ROCK at will. Interestingly, in patient wound samples ROCK is activated at wound margins in rapidly healing wounds and the converse is true of chronic wounds that heal slowly. We are working to identify the mechanism by which ROCK activation regulates the wound healing process with a view to identifying therapeutic targets to promote the healing of chronic wounds.
Click HERE to watch a recent interview by ABC News 24 regarding our research on wound healing.