Cancers exhibit microenvironments that are distinct from those of normal tissues and that strongly promote tumour progression. We have previously shown using a gene-targeted mouse model (K14-ROCK:ER) expressing conditionally active Rho kinase (ROCK), the major RhoA/C-effector protein, that elevated intra-cellular actomyosin tension within the epidermis promotes squamous cell carcinoma (SCC) formation. These SCCs are dependent on increased collagen deposition and remodelling within the extra-cellular matrix (ECM) leading to elevated tissue stiffness and perturbed epidermal homeostasis by the stabilisation of the mechano-responsive transcription factor β-catenin. We have since also shown that fibronectin and periostin – key tumour-promoting components of the ECM – are also elevated within the dermis of K14-ROCK:ER mice in a ROCK-dependent manner. Furthermore, in a collection of human cutaneous SCCs, we observed quantifiable activation of ROCK that correlated with tumour progression and progressively increased collagen, fibronectin and periostin within the ECM, accompanied by activated β-catenin, confirming the clinical relevance of ECM remodelling in this form of cancer.
Regulation of the microenvironment also plays a key role in skin wound healing. In a mouse model deficient for the pleiotropic, phospho-serine binding protein 14-3-3ζ, we observed 3-fold faster re-epithelialisation of incisional wounds compared to wild-type mice. The rapid re-epithelialisation was characterised by elevated ROCK activation at wound margins and increased production/impaired remodelling of the ECM compared to wild-type mice. Interestingly, conditional activation of ROCK in K14-ROCK:ER mice phenocopied 14-3-3ζ deficiency, suggesting that ROCK-mediated changes in ECM composition and stiffness can regulate wound healing kinetics and that 14-3-3ζ functions in a non-redundant manner to restrain ROCK activation at wound margins.
These observations add to increasing evidence that the tissue microenvironment represents a new target in the treatment of disease. Our data suggest that ROCK inhibition should be explored as a therapeutic approach for the treatment of cutaneous SCC by targeting and normalising the tumour microenvironment, while 14-3-3ζ inhibition may have therapeutic utility in the treatment of wounds.