The molecular mechanisms by which the Rho-ROCK pathway promotes mechano-reciprocity and tumour progression
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 have established that ROCK activity promotes tumour progression.
We have since 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 and have identified key molecular players that mediate fibroblast education downstream of ROCK activity in tumours. These mediators cause fibroblasts to produce tumour-promoting factors and ECM components and may be useful as new targets to normalise the tumour microenvironment.
How does the Rho-ROCK pathway generate a tumour-permissive immune 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, but also leads to the recruitment of tumour-promoting immune cells, 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 and cancer progression?
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.
We have also established that compressive stress enhances Rho-ROCK pathway activation in tumour cells and normal tissues (Small GTPases, In Press, 2019). We are now working on identifying the mediators linking compressive stress to Rho activation, which may be useful in moderating tumour progression.
Click HERE to watch an interview by ABC News 24 regarding our research on wound healing.