Compressive forces activate RHO/ROCK-mediated cellular processes characteristic of disease states

Boyle ST1, Kular J1, Nobis M2, Timpson P2 and Samuel MS1

  1. Centre for Cancer Biology, University of South Australia and SA Pathology, Adelaide, SA Australia.
  2. The Kinghorn Cancer Centre & Garvan Institute of Medical Research & St. Vincent’s Clinical School, Victoria St, Darlinghurst, NSW Australia.

Mechanical forces exerted by the extracellular matrix (ECM) upon cells during homeostatic development are counterbalanced by intracellular forces mediated via mechanotransduction signalling pathways that regulate remodelling and tension of the actomyosin cytoskeleton. This phenomenon is termed mechano-reciprocity. The main regulator of these cytoskeletal dynamics is myosin II, and its regulatory subunit myosin regulatory light chain-2 (MLC2) can be directly activated by the RHO/ROCK signalling pathway. Enhanced extracellular matrix tension in diseased states such as cancer enhances mechanotransduction, and so understanding the phenomenon of mechano-reciprocity and its regulation during homeostasis is key to understanding how these processes become corrupted in disease. We have found that acute compressive force applied to cells and epithelial tissues is able to activate the RHO/ROCK signalling pathway, elevating RHOA-GTP levels and increasing regulatory myosin phosphorylation, actomyosin contractility and tension via ROCK. In consequence, cell proliferation was increased, as was the expression of regulators of epithelial-mesenchymal transition. Pharmacological inhibition of ROCK abrogated myosin phosphorylation, whilst inhibition of either RHO or ROCK reversed the physiological effects of compression on cells. Our results strongly suggest that RHO/ROCK-mediated mechanical signalling during cancer, induced by compressive stress from tumour growth within a constricted space, could play a role in tumour progression.