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Cited by 3,941Cellular Mechanics and InteractionsCell Adhesion Molecules ResearchProtein Kinase Regulation and GTPase Signaling

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Tensional homeostasis and the malignant phenotype

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Paszek, Matthew J., Zahir, Nastaran, Johnson, Kandice R., Lakins, Johnathon N., Rozenberg, Gabriela I., Gefen, Amit, Reinhart-King, Cynthia A., Margulies, Susan S., Dembo, Micah, Boettiger, David, Hammer, Daniel A., Weaver, Valerie M.·2005·Cancer Cell
DOI 10.1016/j.ccr.2005.08.010
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Abstract

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.

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Metadata

Authors
Paszek, M. J., Zahir, N., Johnson, K. R., Lakins, J. N., Rozenberg, G. I., Gefen, A., Reinhart-King, C. A., Margulies, S. S., Dembo, M., Boettiger, D., Hammer, D. A., & Weaver, V. M.
Affiliations
  • University of Pennsylvania (US)
  • Tel Aviv University (IL)
  • Boston University (US)
Corresponding author
Weaver, Valerie M.
ORCID
Venue
Cancer Cell
Publisher
Elsevier BV
Published
2005-09
Volume
8
Issue
3
Pages
241-254
ISSN
1535-6108 (ISSN-L)
DOI
10.1016/j.ccr.2005.08.010
OpenAlex
W2099052265
Cited by
3,941
References
0
Citations by year
2026: 142 · 2025: 165 · 2024: 155 · 2023: 172 · 2022: 193 · 2021: 221 · 2020: 273 · 2019: 217 · 2018: 262 · 2017: 256 · 2016: 239 · 2015: 249 · 2014: 225 · 2013: 237 · 2012: 183
FWCI
33.71
Type
journal article
Language
en
Open access
Licence
Locations
  • Cancer Cell (publishedVersion)
  • PubMed (publishedVersion)
Funders
  • Ministerio de Economía y Competitividad
  • National Heart, Lung, and Blood Institute (R01HL057204, HL-57204, HL64388-01A1, T32HL007954, T32HL00795404)
  • National Cancer Institute (R01CA078731, CA078731)
  • National Institute of General Medical Sciences (R01GM057388, GM57388)
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
  • Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Protein Kinase Regulation and GTPase Signaling
Keywords
tumor stiffness, extracellular matrix stiffness, integrins, mechanotransduction, cytoskeletal tension, Rho GTPase signaling, ERK activation, focal adhesions, adherens junctions, tissue polarity, epithelial morphogenesis, tumor stroma, contractility, malignant phenotype
MeSH terms
Animals, Cytoskeleton, Homeostasis, Neoplasms, Phenotype, Stress, Mechanical, 3T3 Cells, Stromal Cells, Cell Line, Tumor, Cell Shape, Mice

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