Actomyosin-Mediated Cellular Tension Drives Increased Tissue Stiffness and β-Catenin Activation to Induce Epidermal Hyperplasia and Tumor Growth

SummaryTumors and associated stroma manifest mechanical properties that promote cancer. Mechanosensation of tissue stiffness activates the Rho/ROCK pathway to increase actomyosin-mediated cellular tension to re-establish force equilibrium. To determine how actomyosin tension affects tissue homeostasis and tumor development, we expressed conditionally active ROCK2 in mouse skin. ROCK activation elevated tissue stiffness via increased collagen. β-catenin, a key element of mechanotranscription pathways, was stabilized by ROCK activation leading to nuclear accumulation, transcriptional activation, and consequent hyperproliferation and skin thickening. Inhibiting actomyosin contractility by blocking LIMK or myosin ATPase attenuated these responses, as did FAK inhibition. Tumor number, growth, and progression were increased by ROCK activation, while ROCK blockade was inhibitory, implicating actomyosin-mediated cellular tension and consequent collagen deposition as significant tumor promoters.

Graphical AbstractFigure optionsDownload full-size imageDownload high-quality image (238 K)Download as PowerPoint slideHighlights► Collagen deposition and tissue stiffness induced by cellular actomyosin contraction ► ROCK-induced actomyosin contractility stimulates β-catenin transcriptional activity ► ROCK-induced proliferation blocked by β-catenin deletion or actomyosin inhibition ► Actomyosin contraction-driven tissue stiffness fosters tumor growth and progression