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

Abstract

SUMMARY 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.

ROCK2/rasHa co-operation induces malignant conversion via p53 loss, elevated NF-κB and tenascin C-associated rigidity, but p21 inhibits ROCK2/NF-κB-mediated progression

“…32,33 Indeed, as outlined below, these K14.ROCK er /HK1.ras 1205 data suggest a mechanism involving p53 loss which links ROCK2-associated NF-κβ deregulation to the matrix remodelling that drives progression [34][35][36][37] when coupled to GSK3β/β-catenin/WNT signalling effects. 5 20,23,41 All wdSCCs exhibited persistent basal-layer p21 expression, which exactly paralleled K14.ROCK er /pMypt1 expression suggesting that increased p21 is a common response to ras/ROCK er /ROCK2 activities. This feature also accounts for malignancy appearing within 10 weeks but progression to SCC required an additional 4-6wks; necessitating both p21 loss and continued ROCK er /ROCK2 activities.…”

“…1,2 ROCK2 acts to regulate cellular motility through phosphorylation of LIM kinases (LIMK), myosin regulatory light chains (MLC2) and myosin-binding subunit to inhibit MLC phosphatase (Mypt1). Thus in carcinogenesis, deregulated ROCK2 signalling and Mypt1 inactivation increases actomyosin-mediated cellular tension and collagen deposition that alters the extracellular matrix [ECM] to increase tissue rigidity, [3][4][5][6][7][8] alongside increased cell contractibility/motility that facilitates invasion. [4][5][6] This increased matrix density changes integrin clustering and increases proliferation via signalling through FAK downregulates GSK3β and increases β-catenin; 5,6 whilst additional signal transduction pathways 9-12 provide a matrix permissive for tumour progression.…”

“…Thus in carcinogenesis, deregulated ROCK2 signalling and Mypt1 inactivation increases actomyosin-mediated cellular tension and collagen deposition that alters the extracellular matrix [ECM] to increase tissue rigidity, [3][4][5][6][7][8] alongside increased cell contractibility/motility that facilitates invasion. [4][5][6] This increased matrix density changes integrin clustering and increases proliferation via signalling through FAK downregulates GSK3β and increases β-catenin; 5,6 whilst additional signal transduction pathways 9-12 provide a matrix permissive for tumour progression. [4][5][6]13 This association with invasion and metastasis, plus the fact that ROCK proteins act as effectors downstream of ras signalling, make ROCK inhibition an attractive therapeutic target; 3,8 particularly since ras-specific inhibitors have proved unsuccessful.…”

“…[4][5][6] This increased matrix density changes integrin clustering and increases proliferation via signalling through FAK downregulates GSK3β and increases β-catenin; 5,6 whilst additional signal transduction pathways 9-12 provide a matrix permissive for tumour progression. [4][5][6]13 This association with invasion and metastasis, plus the fact that ROCK proteins act as effectors downstream of ras signalling, make ROCK inhibition an attractive therapeutic target; 3,8 particularly since ras-specific inhibitors have proved unsuccessful. 14 However, few transgenic studies have directly explored activated ROCK2/ras Ha synergism.…”

Novel signatures of cancer‐associated fibroblasts

“…The same study also suggested that tumor number growth and progression were increased by ROCK activation, whereas ROCK blockade was inhibitory. 20 EGLN1-EGL nine homolog 1 or hypoxia-inducible factor prolyl hydroxylase 2…”