The extra-cellular matrix (ECM) is a source of biochemical and biomechanical influences that direct cell proliferation and fate. However, the molecular mechanisms that regulate the interplay between these influences and tissue homeostasis are still relatively ill-defined. In particular, while cancer cells forming tumours of epithelia origin do not themselves synthesise substantial amounts of ECM proteins, they strongly influence genetically normal cells within the tumour microenvironment to do so, resulting in a dense ECM, configured for tumour-promotion.
The Rho-ROCK signalling pathway lies at the interface between mechanical and biochemical signalling. ROCK signalling promotes tumour progression by enhancing the production of ECM proteins such as collagen, fibronectin, periostin and tenascin C, thereby elevating ECM stiffness and enhancing integrin-mediated mechanotransduction signalling in tumours. We have demonstrated that that tumours in which ROCK is activated exhibit a characteristic secretome that mediates the recruitment, activation and education of key cell types within the microenvironment.
I will discuss insights that we have gained into this process, including our discovery of the ROCK-PERK-CRELD2 signalling axis, the role of compressive stress in activating a tumour-promoting positive feedback loop of mechanotransduction that may be therapeutically targetable and the intriguing cell physiological changes in CAFs that may underpin their behaviour.