Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth.

TitleActomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth.
Publication TypeJournal Article
Year of Publication2011
AuthorsSamuel 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
JournalCancer Cell
Volume19
Issue6
Pagination776-91
Date Published2011 Jun 14
ISSN1878-3686
KeywordsActomyosin, 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.

DOI10.1016/j.ccr.2011.05.008
Alternate JournalCancer Cell
PubMed ID21665151
PubMed Central IDPMC3115541
Grant List15566 / / 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