Tensional homeostasis and the malignant phenotype.
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.
Paszek
Matthew J
MJ
Department of Bioengineering, University of Pennsylvania, Philadelphia, 19104, USA.
Zahir
Nastaran
N
Johnson
Kandice R
KR
Lakins
Johnathon N
JN
Rozenberg
Gabriela I
GI
Gefen
Amit
A
Reinhart-King
Cynthia A
CA
Margulies
Susan S
SS
Dembo
Micah
M
Boettiger
David
D
Hammer
Daniel A
DA
Weaver
Valerie M
VM
D016475:3T3 Cells; D000818:Animals; D045744:Cell Line, Tumor; D048430:Cell Shape; D003599:Cytoskeleton / Q000502:physiology; D006706:Homeostasis / Q000502:physiology*; D051379:Mice; D009369:Neoplasms / Q000235:genetics* / Q000473:pathology / Q000503:physiopathology; D010641:Phenotype; D013314:Stress, Mechanical; D017154:Stromal Cells / Q000473:pathology / Q000502:physiology