1. Actomyosin-Mediated Cellular Tension Drives Increased Tissue Stiffness and β-Catenin Activation to Induce Epidermal Hyperplasia and Tumor Growth
- Author
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Daniel R. Croft, Michael F. Olson, Owen J. Sansom, Nick Barker, Paul Timpson, June Munro, Jose Lopez, Valerie M. Weaver, Michael S. Samuel, Hans Clevers, Valerie G. Brunton, Ewald Schroder, Ewan J. McGhee, David Strachan, Kurt I. Anderson, Jing Zhou, Samuel, Michael S, Lopez, Jose I, McGhee, Ewan J, Croft, Daniel R, Strachan, David, Timpson, Paul, Munro, June, Schroder, Ewald, Zhou, Jing, Brunton, Valerie G, Barker, Nick, Clevers, Hans, Sansom, Owen J, Anderson, Kurt I, Weaver, Valerie M, Olson, Michael F, and Hubrecht Institute for Developmental Biology and Stem Cell Research
- Subjects
Cancer Research ,medicine.medical_specialty ,Skin Neoplasms ,Beta-catenin ,Myosin ATPase ,macromolecular substances ,Article ,Contractility ,epidermal hyerplasia ,Mice ,03 medical and health sciences ,0302 clinical medicine ,Internal medicine ,medicine ,Animals ,Humans ,ROCK2 ,Cells, Cultured ,beta Catenin ,Tissue homeostasis ,Cell Proliferation ,030304 developmental biology ,actomyosin-mediated cellular tension ,rho-Associated Kinases ,0303 health sciences ,Hyperplasia ,Papilloma ,Mechanosensation ,biology ,beta-catenin ,Cell Biology ,Actomyosin ,Biomechanical Phenomena ,3. Good health ,Cell biology ,tumor growth ,Endocrinology ,Oncology ,030220 oncology & carcinogenesis ,Catenin ,biology.protein ,Epidermis ,Signal transduction ,Signal Transduction - Abstract
Tumors 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. beta-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. [KEYWORDS: Actomyosin/ physiology, Animals, Biomechanics, Cell Proliferation, Cells, Cultured, Epidermis/ pathology, Humans, Hyperplasia, Mice, Papilloma/etiology, Signal Transduction, Skin Neoplasms/ etiology, beta Catenin/ physiology, rho-Associated Kinases/analysis/genetics/physiology]
- Published
- 2011
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