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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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Matrix stiffness drives alterations in aldehyde metabolism, inducing DNA damage and transformation
Jones, M., Percival, H., Hales, A., Wood, A., Sun, H.-Y., Tennant, F., Broadberry, E., Skaria, E., Barnes, H. W., Zindy, E., et al. (2025) · Scientific Reports · doi:10.1038/s41598-025-12880-0 · Cited by 3
“Both normal and transformed MECs undergo phenotypic changes in response to the mechanical stiffness of their microenvironment 9,13,14 .”
Garcia‐Herreros, A., Yeh, Y., Tu, Y., Kandasamy, A., del Álamo, J. C., & Criado-Hidalgo, E. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.08.041 · Cited by 6
Beber, L., Lamon, E., Moretti, G., Saveriano, M., Fambri, L., Palopoli, L., & Fontanelli, D. (2025) · IEEE Transactions on Instrumentation and Measurement · doi:10.1109/tim.2025.3581663 · Cited by 3
“To illustrate this point, consider the example of healthy breast tissue, its elastic modulus is 20 times less than the modulus of diseased tissue [41], [42].”
Yan, F., Göransson, S., Olofsson, H., Vogiatzakis, C., Acharekar, A., & Strömblad, S. (2025) · bioRxiv · doi:10.1186/s12964-025-02276-y · Cited by 3
“These results are in agreement with early studies showing that cues from a normal microenvironment can revert malignant cells to a more normal phenotype [26, 28] as well as seminal work describing the effects of matrix stiffness on breast cancer progression [18, 29].”
Effect of elastic modulus of tumour and non-tumour cells on vibration-induced behaviours
Ku, B., Liu, J., Na, S., Yokota, H., Hong, C., & Lim, H.-C. (2025) · Scientific Reports · doi:10.1038/s41598-025-97837-z · Cited by 3
“responses across a range of elastic moduli, this study provides insights into how low-intensity vibrations differentially affect tumour-like and normal cells 16 .”
Sharma, A., Steger, R. F., Li, J. M., Baude, J. A., Heom, K. A., Dey, S. S., & Stowers, R. S. (2025) · bioRxiv · doi:10.1101/2025.03.18.643983 · Cited by 3
Baude, J. A., Li, M. D., Jackson, S. M., Sharma, A., Walter, D. I., & Stowers, R. S. (2025) · bioRxiv · doi:10.1101/2025.02.28.640825 · Cited by 3
“While the literature extensively documents the impacts of matrix stiffness in vivo and in vitro (17,18,20–22), viscoelasticity has received less attention in the context of mammary epithelium, though recent studies demonstrate that viscoelasticity can impact mammary epithelial and breast cancer…”
Sun, X.-S., Liu, L., Li, Y., Du, C., Sun, R., Luo, D., Li, L., Chen, Q.-Y., Tang, L., & Mai, H. (2024) · Precision medicine and engineering. · doi:10.1016/j.preme.2024.100005 · Cited by 2
The study on 4D culture system of squamous cell carcinoma of tongue
Xing, Y., Wang, Y., Wang, R., Sun, X., Zhang, M., Tian, W., & Jing, G. (2024) · Biomedical Materials · doi:10.1088/1748-605x/ad7555 · Cited by 3
“For example, studies have found that tissue stiffness in breast cancer exceeds 4 KPa [29].”
Restoring mechanophenotype reverts malignant properties of ECM-enriched vocal fold cancerPreprint
Kaivola, J., Punovuori, K., Chastney, M. R., Miroshnikova, Y. A., Abdo, H., Bertillot, F., Krautgasser, F., Franco, J. D., Conway, J. R. W., Follain, G., et al. (2024) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2024.08.22.609159 · Cited by 2
“In recent years, there has been a growing appreciation of the role of ECM remodeling and increased ECM deposition in cancer pathogenesis 8,9 as the ensuing increase in tissue rigidity alters tissue mechanics and drives cancer progression 10–13 .”
BackgroundCheung, B. C. H., Chen, X., Davis, H. J., Nordmann, C. S., Toth, J. M., Hodgson, L., Segall, J. E., Shenoy, V. B., & Wu, M. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.10.24.563860 · Cited by 3
“In human breast carcinoma, it has been reported that tumor malignancy can be driven by ECM stiffness(3), and aligned collagen fibers perpendicular to the tumor boundary were found to correlate with poor survival(4).”
BackgroundDivergent iron regulatory states contribute to heterogeneity in breast cancer aggressiveness
Leineweber, W. D., Rowell, M. Z., Ranamukhaarachchi, S. K., Walker, A., Li, Y., Villazon, J. I., Mestre‐Farrera, A., Hu, Z., Yang, J., Shi, L., et al. (2024) · iScience · doi:10.1016/j.isci.2024.110661 · Cited by 6
“15 19 Bulk RNAsequencinganalysis has shown that cancercells upregulate a transcriptional program that is predictive of poor prognosis when embedded in dense collagen type I prior to undergoing collective invasion, and this response is related to oxidative stress.”
Simsek, A. N., Koch, M. D., Sanfilippo, J. E., Gitai, Z., Gompper, G., & Sabass, B. (2023) · bioRxiv · doi:10.1101/2023.05.09.538458 · Cited by 3
“Examples include the epithelial mesenchymal transition, cancer metastasis [1, 2], immune-cell migration [3], and bacterial infection [4–7].”
Gaietta, G. M., Kai, F., Swift, M. F., Weaver, V. M., Volkmann, N., & Hanein, D. (2022) · Molecular Biology of the Cell · doi:10.1091/mbc.e22-03-0092 · Cited by 5
“These model systems were coupled with molecular and pharmacological manipulations to identify key regulators of mechanotransduction (Pelham and Wang, 1997; Wang and Pelham, 1998; Kai et al. , 2021) and used to examine the impact of ECM stiffness on oncogenic transformation (Paszek et al. , 2005).”
Self-citationMelcher, M., Block, I., Kropf, K., Singh, A. K., & Posern, G. (2022) · Cell Communication and Signaling · doi:10.1186/s12964-022-00977-2 · Cited by 3
“The stiffer matrix slightly elevated the rate of luminal filling also in control organoids, consistent with previous reports [4], but this was strongly exacerbated in 4OHT-treated tg organoids showing a profound loss of hollow acinar structures (Fig.”
BackgroundResultInfluentialIngavle, G. C., & Das, D. M. (2022) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.2c00484 · Cited by 3
Yang, A., Zhou, H.-J., Tang, T., Luo, J.-K., & Cui, H.-J. (2022) · Science in progress · doi:10.1177/00368504221115509 · Cited by 3
“Among the MMP family, MMP-2, MMP-9, and MT1-MMP are of particular interest in angiogenesis.(11,12,15,16) In this study, we aimed to examine the impact of ICH on ECM-related genes using a DNA microarray.”
MethodTensin 2-deficient nephropathy: mechanosensitive nephropathy, genetic susceptibility
Sasaki, H., & Sasaki, N. (2022) · EXPERIMENTAL ANIMALS · doi:10.1538/expanim.22-0031 · Cited by 3
Balancin, M. L., Baldavira, C. M., Prieto, T. G., Rúgolo, J. R. M., Farhat, C., Assato, A. K., Velosa, A. P. P., Teodoro, W. R., Ab’Saber, A. M., Takagaki, T. Y., et al. (2022) · Frontiers in Medicine · doi:10.3389/fmed.2022.871202 · Cited by 3
“Augmented ECM stiffness and increasing core matrisome factors also disrupt stroma morphogenesis, thus helping develop a specific malignant phenotype in tumor cell populations (34).”
BackgroundEngineering tumor constructs to study matrix-dependent angiogenic signaling of breast cancer cells
Nasser, M. M., & Ghosh, G. (2022) · Biotechnology progress (Print) · doi:10.1002/btpr.3250 · Cited by 3
Nascent Adhesion Clustering: Integrin-Integrin and Integrin-Substrate Interactions
Lin, K., & Asaro, R. (2022) · Biophysica · doi:10.3390/biophysica2010004 · Cited by 3
“…environment, e.g., stiffness [1–6] and even topography [7–10], as they proliferate [11], differentiate [2], migrate [1], as well as engage in the vital processes of cell development [12,13], including, inter alia, tumorgenesis [14,15], cell growth [16–18] and wound healing [19,20], inter alia.”
Sikander, S., Biswas, P., & Song, S.-E. (2021) · Micromachines · doi:10.3390/mi12050576 · Cited by 3
“Differences in size and stiffness of a tumor may provide information about the early initiation of the disease or its severity, and a physician’s expertise is critical to distinguish the severity of the tumor [2,4,7,8,10].”
BackgroundWatchaputi, K., Somboon, P., Phromma-in, N., Ratanakhanokchai, K., & Soontorngun, N. (2021) · Scientific Reports · doi:10.1038/s41598-021-87342-4 · Cited by 3
Impact of Experimental Parameters on Cell–Cell Force Spectroscopy Signature
Oropesa‐Nuñez, R., Mescola, A., Vassalli, M., & Canale, C. (2021) · Sensors · doi:10.3390/s21041069 · Cited by 5
Local strong acids: A driving force for metastasis.
Wan, Y., Ma, X., Li, Y., Huang, X., Gan, T., Xu, L., Cao, W.-G., & Liu, Q. (2020) · Medical Hypotheses · doi:10.1016/j.mehy.2020.110221 · Cited by 3
Choi, S., Oleksyuk, V., Caroline, D., Pascarella, S., Kendzierski, R., & Won, C.-H. (2020) · Annual International Conference of the IEEE Engineering in Medicine and Biology Society · doi:10.1109/embc44109.2020.9176636 · Cited by 3
Valadão, I., Ralph, A. C. L., Bordeleau, F., Dzik, L. M., Borbely, K., Geraldo, M., Reinhart-King, C., & Freitas, V. (2020) · PeerJ · doi:10.7287/peerj.9153v0.2/reviews/1
Self-citationWu, M., Xu, D., Dou, X., Zhou, Y., Lu, J., & Ge, Q. (2026) · Cell Signaling Inflammation & Disease · doi:10.1186/s44505-026-00004-y · Cited by 2
“These mechanical stresses are sensed by tumor cells through mechanotransduction pathways, thereby modulating cell behavior [12, 13].”
Engineering the fourth dimension of cell-instructive hydrogels through dynamic bonding.
Xiao, R., & Webber, M. J. (2026) · Journal of Controlled Release · doi:10.1016/j.jconrel.2026.115132 · Cited by 2
Liu, B., Liu, X., Wang, Y., Han, X., & Dang, X. (2026) · Frontiers in Pharmacology · doi:10.3389/fphar.2026.1699709 · Cited by 1
“…documented that solid tumors exhibit elevated interstitial fluid pressure, increased tissue stiffness, and abnormal solid stress, establishing that the physical tumor microenvironment is profoundly different from that of normal tissue (Jain, 1987; Helmlinger et al., 1997; Paszek et al., 2005).”
InfluentialIntegrin α2: mode of regulation and functioning in the metastatic cancer cascade
Wang, L., Sun, M., Zhu, H., Deng, H.-L., Zhang, S.-C., & Sun, C.-G. (2026) · Journal of Translational Medicine · doi:10.1186/s12967-026-07987-5 · Cited by 2
“After maturation of FAs, mechanical signals are converted into chemical signals by recruiting and activating key signalling molecules such as FAK [66], Paxillin [67], SRC [68] and ERK [69].”
Sreedasyam, R., Vu, E. C., Thota, S., Botvinick, E. L., & Venugopalan, V. (2026) · Acta Biomaterialia · doi:10.1016/j.actbio.2026.03.024 · Cited by 2
Mechanical instability as a signature of viscoelastic decoupling at the tumor–brain interface
Aunan-Diop, J. S., Friismose, A., Hojo, E., Yin, Z.-Y., Halle, B., Harbo, F., Mussmann, B., & Poulsen, F. (2026) · Biomaterials Advances · doi:10.1016/j.bioadv.2026.214758 · Cited by 2
Du, X., Lin, Z., Zeng, Y., & Chen, C. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1752590 · Cited by 1
“In the early stages of malignant transformation, enhanced intracellular actin polymerization and stress fiber formation lead to reduced overall cellular flexibility and increased rigidity (Paszek et al., 2005).”
Zhao, L., Han, Y., Du, J., & Zhao, X. (2026) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2026.113170 · Cited by 2
Qian, G., Zhang, H., Zahm, C. D., & Provenzano, P. P. (2026) · Current Opinion in Biomedical Engineering · doi:10.1016/j.cobme.2026.100651 · Cited by 3
Ooms, L. M., Ferguson, D. T., Rodgers, S. J., Sukhija, K. K., Jones, E. I., Csolle, M. P., Yip, H. Y. K., Daly, R. J., Tiganis, T., McLean, C., et al. (2025) · Communications Biology · doi:10.1038/s42003-025-09364-2 · Cited by 3
“Increased matrix stiffness promotes mammary epithelial cell transformation and enhances tumor cell invasion and dissemination 44 – 46 .”
Cellular mechanosensing on a cell-scale stiffness gradient substrate.
Bhattacharjee, I., Soni, G. V., & Sarangi, B. R. (2025) · Soft Matter · doi:10.1039/d5sm00592b · Cited by 2
Extracellular matrix cues as drivers of liver zonation: A framework for in vitro biomaterial design
Criel, H., Grootaert, C., & Camp, J. V. (2025) · Acta Biomaterialia · doi:10.1016/j.actbio.2025.12.015 · Cited by 2
Gato-Diaz, U., Alves, L. D. C., Concheiro, Á., Piñeiro, Y., Alvarez‐Lorenzo, C., Blanco‐Fernandez, B., & Rivas, J. M. (2025) · International Journal of Biological Macromolecules · doi:10.1016/j.ijbiomac.2025.149205 · Cited by 3
Gupta, S., Patni, K., Kaur, S., & Dhanjal, J. K. (2025) · Journal of Translational Medicine · doi:10.1186/s12967-025-07153-3 · Cited by 2
“Activation of these signaling routes leads to enhanced cytoskeletal dynamics via ROCK/Rho and Myosin II (upregulated), promoting nuclear translocation of key transcription factors [43].”
McCue, C., Lee, W.-H., Vandereydt, B. J. C., Avalle, D., Kang, J.-M., Rufer, S., Atari, A., Dickhardt, F. J., Nitzsche, M., Parks, S., et al. (2025) · ACS Nano · doi:10.1021/acsnano.5c09950 · Cited by 2
Self-organization of tumor heterogeneity and plasticityPreprint
Gonzalez, C. P., Brückner, D. B., Di‐Luoffo, M., Richon, S., Goswami, R., Baghdadi, M. B., Piastra-Facon, F., Felsenthal, N., Bouras, R., Fumagalli, A., et al. (2025) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2025.10.09.681487 · Cited by 2
Actin rings as mechanical barriers in endothelial resistance to tumor invasion
Jiang, C., Xie, G., Wang, Q., & Ji, B. (2025) · Cell Reports Physical Science · doi:10.1016/j.xcrp.2025.102898 · Cited by 2
Batur, L. K., Yavaş, C., & Hekim, N. (2025) · Oncology Letters · doi:10.3892/ol.2025.15306 · Cited by 2
“Beyond merely transmitting signals, the ECM also generates biochemical and biophysical cues that activate cellular responses (4).”
Jadhav, D., Knapinska, A. M., Wang, H., & Fields, G. B. (2025) · Biomolecules · doi:10.3390/biom15081114 · Cited by 3
“Extracellular matrix stiffness occurs in the tumor microenvironment [55,56] (Paszek 2005 & Levental 2009).”
Senarathne, D. S., Shahu, L., & Lu, H. P. (2025) · Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.5c00800 · Cited by 2
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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