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

Michael S. Samuel; Jose I. Lopez; Ewan J. McGhee; Daniel R. Croft; David Strachan; Paul Timpson; June Munro; Ewald Schröder; Jing Zhou; Valerie G. Brunton; Nick Barker; Hans Clevers; Owen J. Sansom; Kurt I. Anderson; Valerie M. Weaver; Michael F. Olson

doi:10.1016/j.ccr.2011.05.008

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

Michael S. Samuel, Jose I. Lopez, Ewan J. McGhee, Daniel R. Croft, David Strachan, Paul Timpson, June Munro, Ewald Schröder, Jing Zhou, Valerie G. Brunton, Nick Barker, Hans Clevers, Owen J. Sansom, Kurt I. Anderson, Valerie M. Weaver, Michael F. Olson

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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.

Original language	English
Pages (from-to)	776-791
Number of pages	16
Journal	Cancer Cell
Volume	19
Issue number	6
DOIs	https://doi.org/10.1016/j.ccr.2011.05.008
Publication status	Published - 14 Jun 2011
Externally published	Yes

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Samuel, M. S., Lopez, J. I., McGhee, E. J., Croft, D. R., Strachan, D., Timpson, P., Munro, J., Schröder, E., Zhou, J., Brunton, V. G., Barker, N., Clevers, H., Sansom, O. J., Anderson, K. I., Weaver, V. M., & Olson, M. F. (2011). Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth. Cancer Cell, 19(6), 776-791. https://doi.org/10.1016/j.ccr.2011.05.008

@article{67c84e2244d04be8904c1c588954334f,

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.",

author = "Samuel, {Michael S.} and Lopez, {Jose I.} and McGhee, {Ewan J.} and Croft, {Daniel R.} and David Strachan and Paul Timpson and June Munro and Ewald Schr{\"o}der and Jing Zhou and Brunton, {Valerie G.} and Nick Barker and Hans Clevers and Sansom, {Owen J.} and Anderson, {Kurt I.} and Weaver, {Valerie M.} and Olson, {Michael F.}",

note = "Funding Information: We acknowledge the support of the Think Pink breast cancer group who funded purchase of the NDP slide scanner. Thanks to Martin Stockley for LIMKi synthesis. Funding for this study was from Cancer Research UK (M.F.O.), IRACDA Scholars in Science K12GM081266 award (J.I.L.), W81XWH-05-1-0330 from the DOD BCRP and CA138818-01A1 from the NCI (V.M.W.). ",

year = "2011",

month = jun,

day = "14",

doi = "10.1016/j.ccr.2011.05.008",

language = "English",

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pages = "776--791",

journal = "Cancer Cell",

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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 2011, 'Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth', Cancer Cell, vol. 19, no. 6, pp. 776-791. https://doi.org/10.1016/j.ccr.2011.05.008

TY - JOUR

T1 - Actomyosin-mediated cellular tension drives increased tissue stiffness and β-catenin activation to induce epidermal hyperplasia and tumor growth

AU - Samuel, Michael S.

AU - Lopez, Jose I.

AU - McGhee, Ewan J.

AU - Croft, Daniel R.

AU - Strachan, David

AU - Timpson, Paul

AU - Munro, June

AU - Schröder, Ewald

AU - Zhou, Jing

AU - Brunton, Valerie G.

AU - Barker, Nick

AU - Clevers, Hans

AU - Sansom, Owen J.

AU - Anderson, Kurt I.

AU - Weaver, Valerie M.

AU - Olson, Michael F.

N1 - Funding Information: We acknowledge the support of the Think Pink breast cancer group who funded purchase of the NDP slide scanner. Thanks to Martin Stockley for LIMKi synthesis. Funding for this study was from Cancer Research UK (M.F.O.), IRACDA Scholars in Science K12GM081266 award (J.I.L.), W81XWH-05-1-0330 from the DOD BCRP and CA138818-01A1 from the NCI (V.M.W.).

PY - 2011/6/14

Y1 - 2011/6/14

N2 - 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.

AB - 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.

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AN - SCOPUS:79958735965

SN - 1535-6108

VL - 19

SP - 776

EP - 791

JO - Cancer Cell

JF - Cancer Cell

IS - 6

ER -

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

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