Tensional homeostasis and the malignant phenotype.

TitleTensional homeostasis and the malignant phenotype.
Publication TypeJournal Article
Year of Publication2005
AuthorsPaszek MJ, Zahir N, Johnson KR, Lakins JN, Rozenberg GI, Gefen A, Reinhart-King CA, Margulies SS, Dembo M, Boettiger D, Hammer DA, Weaver VM
JournalCancer Cell
Date Published2005 Sep
Keywords3T3 Cells, Animals, Cell Line, Tumor, Cell Shape, Cytoskeleton, Homeostasis, Mice, Neoplasms, Phenotype, Stress, Mechanical, Stromal Cells

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.

Alternate JournalCancer Cell
PubMed ID16169468
Grant ListCA078731 / CA / NCI NIH HHS / United States
GM57388 / GM / NIGMS NIH HHS / United States
HL57204 / HL / NHLBI NIH HHS / United States
HL6438801A1 / HL / NHLBI NIH HHS / United States
T32HL00795404 / HL / NHLBI NIH HHS / United States