Title | Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth. |
Publication Type | Journal Article |
Year of Publication | 2011 |
Authors | Samuel MS, Lopez JI, McGhee EJ, Croft DR, Strachan D, Timpson P, Munro J, Schröder E, Zhou J, Brunton VG, Barker N, Clevers H, Sansom OJ, Anderson KI, Weaver VM, Olson MF |
Journal | Cancer Cell |
Volume | 19 |
Issue | 6 |
Pagination | 776-91 |
Date Published | 2011 Jun 14 |
ISSN | 1878-3686 |
Keywords | Actomyosin, Animals, beta Catenin, Biomechanical Phenomena, Cell Proliferation, Cells, Cultured, Epidermis, Humans, Hyperplasia, Mice, Papilloma, rho-Associated Kinases, Signal Transduction, Skin Neoplasms |
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. 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. |
DOI | 10.1016/j.ccr.2011.05.008 |
Alternate Journal | Cancer Cell |
PubMed ID | 21665151 |
PubMed Central ID | PMC3115541 |
Grant List | 15566 / / Cancer Research UK / United Kingdom R01 CA030721-05 / CA / NCI NIH HHS / United States R01 CA138818 / CA / NCI NIH HHS / United States / / Cancer Research UK / United Kingdom |