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Tensional homeostasis and the malignant phenotype
Open accessAbstract
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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“Increased tissue stiffness triggers prosurvival and proproliferation signalling in cancer cells99.”
From A framework for advancing our understanding of cancer-associated fibroblasts (2020) · cites this paper as [99]
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Mahadik, P., & Patwardhan, S. (2023) · Archives of Biochemistry and Biophysics · doi:10.1016/j.abb.2023.109624 · Cited by 27
Is Cancer Reversible? Rethinking Carcinogenesis Models—A New Epistemological Tool
Pensotti, A., Bertolaso, M., & Bizzarri, M. (2023) · Biomolecules · doi:10.3390/biom13050733 · Cited by 18
The role of the Na+/Ca2+-exchanger (NCX) in cancer-associated fibroblasts
Loeck, T., & Schwab, A. (2023) · Biological Chemistry · doi:10.1515/hsz-2022-0253 · Cited by 20
Zhang, Y., Dong, Q., An, Q., Zhang, C., Mohagheghian, E., Niu, B., Qi, F., Wei, F., Chen, S., Chen, X., et al. (2022) · Advanced Science · doi:10.1002/advs.202203173 · Cited by 12
Karimnia, V., Stanley, M. E., Fitzgerald, C. T., Rizvi, I., Slack, F. J., & Celli, J. P. (2022) · Photochemistry and Photobiology · doi:10.1111/php.13663 · Cited by 15
Debnath, S., Mukherjee, A., Saha, D., Dash, J., & Chatterjee, T. K. (2021) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2021.04.109 · Cited by 17
Zuniga, K., Gadde, M., Scheftel, J., Senecal, K. J., Cressman, E. N. K., Dyke, M. E. V., & Rylander, M. N. (2021) · International Journal of Hyperthermia · doi:10.1080/02656736.2021.1930202 · Cited by 23
Tissue engineered platforms for studying primary and metastatic neoplasm behavior in bone
Thai, V. L., Griffin, K. H., Thorpe, S. W., Randall, R. L., & Leach, J. K. (2020) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2020.110189 · Cited by 18
“For example, cancerous breast tissues may be 20-fold stiffer, while lung carcinomas may be 30 times stiffer than normal tissue (Joyce et al., 2018; Paszek et al., 2005; Shukla et al., 2016; Umemoto et al., 2014).”
BackgroundEndomembranes: Unsung Heroes of Mechanobiology?
Phuyal, S., & Baschieri, F. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.597721 · Cited by 15
Lycopene enriched tomato extract suppresses chemically induced skin tumorigenesis in mice
Koul, A., Bansal, M. P., Aniqa, A., Chaudhary, H., & Chugh, N. (2019) · International Journal for Vitamin and Nutrition Research · doi:10.1024/0300-9831/a000597 · Cited by 17
Remodeling of Adhesion Network within Cancer Spheroids via Cell–Polymer Interaction
Cho, Y., Yu, S. J., Kim, J., Ko, U. H., Park, E. Y., Choung, J. S., Choi, G., Kim, D., Lee, E., Im, S. G., et al. (2020) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.0c00977 · Cited by 14
Extracellular Matrix in Secondary Palate Development
Logan, S. M., Ruest, L. B., Benson, M. D., & Svoboda, K. K. H. (2019) · The Anatomical Record · doi:10.1002/ar.24263 · Cited by 16
“Many aggressive tumor types stiffen the matrix around them to facilitate cell motility, and this stiffness is associated with increased metastatic ability (Paszek et al., 2005; Northey et al., 2017).”
BackgroundKamal, K. M., Ghazali, A. R., Selvarajah, G. T., Mutalib, N. A., Abu, N., Chua, E. W., & Masre, S. F. (2026) · Molecular Biomedicine · doi:10.1186/s43556-026-00436-1 · Cited by 20
“Meanwhile, in tumorigenesis, excessive ECM remodelling by MMPs and LOXs alters biochemical signalling, enhancing invasiveness and angiogenesis [53, 69].”
Beyond the membrane: rethinking EGFR signaling in physiology and cancer
Jendrisek, G., Mesa, D., Conte, A., Malabarba, M. G., & Sigismund, S. (2026) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-025-06036-6 · Cited by 16
Liu, T., Liang, H., Li, Y., Liao, W., Deng, J., Zhang, L., & Shen, F. (2025) · Discover Oncology · doi:10.1007/s12672-025-02456-9 · Cited by 17
“As studies have shown, tumors tend to be stiffer than normal tissues [4].”
Long, L., Liu, M., Deng, X., Jin, J., Cao, M., Zhang, J., Tao, J., Shen, H., Wang, X., Liu, D., et al. (2024) · Radiology · doi:10.1148/radiol.232242 · Cited by 18
Poonja, S., Pinto, A. F., Lloyd, M. C., Damaghi, M., & Rejniak, K. (2023) · Cells · doi:10.3390/cells12232688 · Cited by 14
“It has been experimentally demonstrated that ECM stiffness elevated 10-fold or more in comparison to normal tissue stiffness, was able to induce invasive behavior in the multi-cellular spheroids derived from a nontumorigenic epithelial cell line [56–58].”
BackgroundAdvanced in vitro models for renal cell carcinoma therapy design
Mieville, V., Griffioen, A. W., Benamran, D. A., & Nowak-Sliwinska, P. M. (2023) · Biochimica et Biophysica Acta (BBA) - Reviews on Cancer · doi:10.1016/j.bbcan.2023.188942 · Cited by 12
Camacho-Gómez, D., Sorzabal-Bellido, I., Ortíz-de-Solórzano, C., García-Aznar, J., & Gómez-Benito, M. (2023) · iScience · doi:10.1016/j.isci.2023.107164 · Cited by 14
“Finally, the stiffness of the extracellular matrix (ECM) plays an important role 38 by balancing the luminal hydrostatic pressure and providing physical cues that regulate cell behavior.”
BackgroundIdentification of the Collagen Types Essential for Mammalian Breast Acinar Structures
Keller, C. R., Ruud, K. F., Martinez, S. R., & Li, W. (2022) · Gels · doi:10.3390/gels8120837 · Cited by 14
“In addition to the compositional capacities of the major ECM collagens in mediating acini formation, the mechanical properties of the collagens could potentially regulate not only the formation, but also the sizes and shapes of the acini structures [30].”
BackgroundCancer cells can be killed mechanically or with combinations of cytoskeletal inhibitors
Tijore, A., Yang, B., & Sheetz, M. P. (2022) · Frontiers in Pharmacology · doi:10.3389/fphar.2022.955595 · Cited by 15
“Further, there are studies that show phenotypic changes of tumor cells with different matrix environments (Paszek et al., 2005) or with modifications of integrin function (Weaver et al.”
BackgroundTransient mechanical interactions between cells and viscoelastic extracellular matrix
Slater, B., Li, J., Indana, D., Xie, Y., Chaudhuri, O., & Kim, T. (2021) · Soft Matter · doi:10.1039/d0sm01911a · Cited by 19
Integrin cross-talk modulates stiffness-independent motility of CD4+ T lymphocytes
Kim, S. H. J., & Hammer, D. (2021) · Molecular Biology of the Cell · doi:10.1091/mbc.e21-03-0131 · Cited by 14
“The mechanical stiffness displayed across the physiological extracellular matrices ranges from pascals to gigapascals (Yang et al. , 2017) in locations varying from lymph nodes to inflamed or diseased tissues such as a tumor microenvironment (Paszek et al. , 2005; Teijeira et al. , 2017).”
Self-citationA new agarose-based microsystem to investigate cell response to prolonged confinement
Prunet, A., Lefort, S., Delanoë‐Ayari, H., Laperrousaz, B., Simon, G., Barentin, C., Saci, S., Argoul, F., Guyot, B., Rieu, J.-P., et al. (2020) · Lab on a Chip · doi:10.1039/d0lc00732c · Cited by 26
Microenvironmental modulation of the developing tumour: an immune‐stromal dialogue
Jones, J. O., Moody, W. M., & Shields, J. D. (2020) · Molecular Oncology · doi:10.1002/1878-0261.12773 · Cited by 16
Kulwatno, J., Gearhart, J., Gong, X., Herzog, N. L., Getzin, M., Skobe, M., & Mills, K. L. (2020) · bioRxiv · doi:10.1101/2020.07.06.190447 · Cited by 14
Tumor-stroma biomechanical crosstalk: a perspective on the role of caveolin-1 in tumor progression
Lolo, F., Jiménez-Jiménez, V., Sánchez‐Álvarez, M., & del Pozo, M. Á. (2020) · Cancer and Metastasis Reviews · doi:10.1007/s10555-020-09900-y · Cited by 16
Wu, L., Wu, G., Wu, D., Hu, W., Du, Q., Lu, Q., Wang, J., Xie, A., Yang, Y., Liu, J., et al. (2025) · Advanced Healthcare Materials · doi:10.1002/adhm.202503515 · Cited by 13
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Harnessing the Biological Responses Induced by Nanomaterials for Enhanced Cancer Therapy
Wang, L., Fu, H., Lin, J., Zhao, M. L., Chen, C., Liao, H., & Duan, Y. (2025) · Aggregate · doi:10.1002/agt2.70080 · Cited by 11
“Moreover, significantly increased collagen deposition and promoted ECM stiffness facilitate cancer cell survival and proliferation [276].”
Periprostatic Adipose Tissue as a Contributor to Prostate Cancer Pathogenesis: A Narrative Review
Drewa, J., Lazar-Juszczak, K., Adamowicz, J., & Juszczak, K. (2025) · Cancers · doi:10.3390/cancers17030372 · Cited by 12
“MMP9 elicit epithelial-to-mesenchymal transition in tumour cells, leading to more aggressive phenotype of cancer [132].”
Yue, W., Zhang, H., Gao, Y., Ding, J., Xue, R., Dong, C., Liu, F., Yang, L., Yang, L., & Li, L. (2024) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2024.167205 · Cited by 16
LATS1 controls CTCF chromatin occupancy and hormonal response of 3D-grown breast cancer cells
Ramírez-Cuéllar, J., Ferrari, R., Sanz, R. T., Valverde-Santiago, M., García-García, J., Nacht, A. S., Castillo, D., Dily, F. L., Neguembor, M. V., Malatesta, M., et al. (2024) · The EMBO Journal · doi:10.1038/s44318-024-00080-x · Cited by 14
“Actually, the non-cellular components of the tumor microenvironment (TME), those that are preserved in spheroids, as the extracellular matrix (ECM), growth factors, cytokines, and chemokines, play a signi fi cant role in cancer progression (Paszek et al, 2005).”
Natural Killer Cell Mechanosensing in Solid Tumors
Lightsey, S. E., & Sharma, B. (2024) · Bioengineering · doi:10.3390/bioengineering11040328 · Cited by 14
Park, S.-W., Lai, J. H. C., Han, X.-Q., Leung, V. W. M., Xiao, P.-Y., Huang, J.-P., & Chan, K. (2024) · Pharmaceutics · doi:10.3390/pharmaceutics16010101 · Cited by 13
“[9,10,13].”
BackgroundInfluentialHuman Breast Organoid Models for Lactation Research
Lee, J., Liu, Y., Ray, E. E., Giuliano, A., & Cui, X.-J. (2023) · Reproduction and Breeding · doi:10.1016/j.repbre.2023.08.003 · Cited by 13
Grudtsyna, V., Packirisamy, S., Bidone, T. C., & Swaminathan, V. (2023) · Life Science Alliance · doi:10.26508/lsa.202301898 · Cited by 13
“We focused on ECM 79 density which allows for precise control of integrin activation, is physiologically relevant and 80 is conducive to high-resolution total internal reflection fluorescence microscopy (TIRF)[29]– 81 [32].”
BackgroundMillán-Salanova, M., & Vicente‐Manzanares, M. (2022) · European Journal of Cell Biology · doi:10.1016/j.ejcb.2022.151236 · Cited by 15
Konar, S., Bolam, S. M., Coleman, B., Dalbeth, N., McGlashan, S. R., Leung, S., Cornish, J., Naot, D., & Musson, D. S. (2022) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2022.800748 · Cited by 13
“While the mechanisms driving the observed changes in TDC growth were not explored as part of this study, there is evidence that cell response to stiffer substrates tend to be driven by Rho-ROCK pathways (Paszek et al., 2005; Mih et al., 2012; Sridharan et al., 2019; Doss et al., 2020).”
BackgroundTang, Y., Zhu, L.-X., Cho, J., Li, X.-Y., & Weiss, S. (2022) · Developmental Cell · doi:10.1016/j.devcel.2022.01.015 · Cited by 13
An emergent Wnt5a/YAP/TAZ regulatory circuit and its possible role in cancer
Astudillo, P. (2021) · Seminars in Cell and Developmental Biology · doi:10.1016/j.semcdb.2021.10.001 · Cited by 14
Wieland, A., Strissel, P. L., Schorle, H. R., Bakırcı, E., Janzen, D., Beckmann, M. W., Eckstein, M., Dalton, P. D., & Strick, R. (2021) · Cancers · doi:10.3390/cancers13205144 · Cited by 15
“031 kPa) [80] supporting tumor cell mediated ECM remodeling.”
BackgroundA competitive advantage through fast dead matter elimination in confined cellular aggregates
Pollack, Y. G., Bittihn, P., & Golestanian, R. (2021) · bioRxiv · doi:10.1088/1367-2630/ac788e · Cited by 13
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)
- 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
- bronze
- doi.org
- 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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