TY - JOUR
T1 - Tensional homeostasis and the malignant phenotype
AU - Paszek, Matthew J.
AU - Zahir, Nastaran
AU - Johnson, Kandice R.
AU - Lakins, Johnathon N.
AU - Rozenberg, Gabriela I.
AU - Gefen, Amit
AU - Reinhart-King, Cynthia A.
AU - Margulies, Susan S.
AU - Dembo, Micah
AU - Boettiger, David
AU - Hammer, Daniel A.
AU - Weaver, Valerie M.
N1 - Funding Information:
We thank T. Springer and J. Takagi for the G429N β1 integrin mutant; Z. Werb for the β1 integrin construct; P. Marinkovich for the BM165 mAb; M. Schwartz for the GST-Rhotekin cDNA; D. Gasser and B. Alston-Mills for help with the mice; W. Lee and P. Janmey for sharing materials; L. Lynch for technical assistance; and R. Assoian for helpful comments. This work was supported by NIH grant CA078731 and DOD grants DAMD1701-1-0368, 1703-1-0496, and W81XWH-05-1-330 to V.M.W.; NIH grants HL57204 (to S.S.M.), GM57388 (to D.B.), BRP HL6438801A1 (to V.M.W. and D.A.H.), and T32HL00795404 (to N.Z. and K.R.J.); and DOD grants DAMD17-01-1-0367 and 17-03-1-0421 to J.N.L. and G.I.R.
PY - 2005/9
Y1 - 2005/9
N2 - Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
AB - Tumors are stiffer than normal tissue, and tumors have altered integrins. Because integrins are mechanotransducers that regulate cell fate, we asked whether tissue stiffness could promote malignant behavior by modulating integrins. We found that tumors are rigid because they have a stiff stroma and elevated Rho-dependent cytoskeletal tension that drives focal adhesions, disrupts adherens junctions, perturbs tissue polarity, enhances growth, and hinders lumen formation. Matrix stiffness perturbs epithelial morphogenesis by clustering integrins to enhance ERK activation and increase ROCK-generated contractility and focal adhesions. Contractile, EGF-transformed epithelia with elevated ERK and Rho activity could be phenotypically reverted to tissues lacking focal adhesions if Rho-generated contractility or ERK activity was decreased. Thus, ERK and Rho constitute part of an integrated mechanoregulatory circuit linking matrix stiffness to cytoskeletal tension through integrins to regulate tissue phenotype.
UR - http://www.scopus.com/inward/record.url?scp=24944547482&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2005.08.010
DO - 10.1016/j.ccr.2005.08.010
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C2 - 16169468
AN - SCOPUS:24944547482
SN - 1535-6108
VL - 8
SP - 241
EP - 254
JO - Cancer Cell
JF - Cancer Cell
IS - 3
ER -