title: Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth.
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.
authors.affiliation: Beatson Institute for Cancer Research, Glasgow, UK.
authors.forename: Michael S
authors.initials: MS
authors.lastname: Samuel
authors.forename: Jose I
authors.initials: JI
authors.lastname: Lopez
authors.forename: Ewan J
authors.initials: EJ
authors.lastname: McGhee
authors.forename: Daniel R
authors.initials: DR
authors.lastname: Croft
authors.forename: David
authors.initials: D
authors.lastname: Strachan
authors.forename: Paul
authors.initials: P
authors.lastname: Timpson
authors.forename: June
authors.initials: J
authors.lastname: Munro
authors.forename: Ewald
authors.initials: E
authors.lastname: Schröder
authors.forename: Jing
authors.initials: J
authors.lastname: Zhou
authors.forename: Valerie G
authors.initials: VG
authors.lastname: Brunton
authors.forename: Nick
authors.initials: N
authors.lastname: Barker
authors.forename: Hans
authors.initials: H
authors.lastname: Clevers
authors.forename: Owen J
authors.initials: OJ
authors.lastname: Sansom
authors.forename: Kurt I
authors.initials: KI
authors.lastname: Anderson
authors.forename: Valerie M
authors.initials: VM
authors.lastname: Weaver
authors.forename: Michael F
authors.initials: MF
authors.lastname: Olson
mesh_terms: D000205:Actomyosin / Q000502:physiology*; D000818:Animals; D001696:Biomechanical Phenomena; D049109:Cell Proliferation; D002478:Cells, Cultured; D004817:Epidermis / Q000473:pathology*; D006801:Humans; D006965:Hyperplasia; D051379:Mice; D010212:Papilloma / Q000209:etiology; D015398:Signal Transduction; D012878:Skin Neoplasms / Q000209:etiology*; D051176:beta Catenin / Q000502:physiology*; D054460:rho-Associated Kinases / Q000032:analysis / Q000235:genetics / Q000502:physiology
chemical_list: D051176:beta Catenin; D000205:Actomyosin; D054460:rho-Associated Kinases