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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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Osmotic pressure induces unexpected relaxation of contractile 3D microtissue
Cappello, G., Wodrascka, F., Marquez-Vivas, G., Radwan, A. E., Anoop, P., Mascheroni, P., Fouchard, J., Fabry, B., Ambrosi, D., Recho, P., et al. (2025) · The European Physical Journal E · doi:10.1140/epje/s10189-025-00497-0 · Cited by 2
“…the tissues for 1 h with either growth medium (control condition), bleb-bistatin (a myosin ATPase inhibitor that lowers cell contractility [36, 58, 59]), lysophosphatidic acid (LPA, a phospholipid stimulant of myosin activity via RhoA activation, which increases cell contractility [60–63]) or…”
Zhou, Y., He, Q., Huang, G., Ouyang, P., Wang, H., Deng, J., Chen, P., Liang, X., Hong, Z., Zhang, X., et al. (2025) · CNS Neuroscience & Therapeutics · doi:10.1111/cns.70333 · Cited by 1
“Stiffness, also known as elasticity or rigidity, has been proven to promote tumor initiation, progression, and invasion [89].”
Exposomal determinants of non-genetic plasticity in tumor initiation
Carra, D., Maas, S. C. E., Seoane, J. A., & Alonso‐Curbelo, D. (2025) · Trends in cancer · doi:10.1016/j.trecan.2025.01.010 · Cited by 2
Sun, X., Wang, X.-H., Wu, B., Yang, Q., Zhu, C.-X., Zhang, H., Li, Q., Zhou, H.-R., Guo, M.-H., Gui, L., et al. (2025) · Science China Materials · doi:10.1007/s40843-024-3216-6 · Cited by 1
Simulation of Constant Rate Loading of Eukaryotic Cells Using Statistical Thermodynamic Methods
Nikitiuk, A. (2024) · Математическая биология и биоинформатика · doi:10.17537/2024.19.304 · Cited by 1
Neelsen, C., Elgeti, T., Meyer, T., Grittner, U., Mödl, L., Furth, C., Geisel, D., Hamm, B., Sack, I., & Garcia, S. M. M. (2024) · Investigative Radiology · doi:10.1097/rli.0000000000001089 · Cited by 1
Cofré, J. (2024) · Journal of Biosciences · doi:10.1007/s12038-024-00445-8 · Cited by 2
“Furthermore, both metastasis (Paszek and Weaver 2004; Paszek et al. 2005; DuFort et al. 2011) and gastrulation (Brunet et al. 2013; Mitrossilis et al. 2017; Pukhlyakova et al. 2018; Bailles et al. 2019) can be triggered by mechanical forces and physical phenomena.”
InfluentialAn accessible instrument for measuring soft material mechanical properties
Unikewicz, B. M., Pincot, A., & Cohen, T. (2025) · Review of Scientific Instruments · doi:10.1063/5.0247364 · Cited by 3
Perivascular cells function as mechano-structural sensors of vascular capillariesPreprint
França, C., Verde, M. E. Q. L., Silva-Sousa, A. C., Mansoorifar, A., Athirasala, A., Subbiah, R., Tahayeri, A., Sousa, M., Fraga, M. A., Visalakshan, R. M., et al. (2024) · bioRxiv · doi:10.1101/2024.02.16.580564 · Cited by 1
Cell Line-Dependent Adhesion and Inhibition of Proliferation on Carbon-Based Nanofilms
Wójcik, B., Zawadzka, K., Sawosz, E., Sosnowska, M., Ostrowska, A., & Wierzbicki, M. (2023) · Nanotechnology, Science and Applications · doi:10.2147/nsa.s439185 · Cited by 1
Takahashi, H., Ito, R., Matsumura, Y., & Sakai, J. (2023) · BioEssays · doi:10.1002/bies.202300084 · Cited by 2
Mediator Subunit Med4 Enforces Metastatic Dormancy in Breast Cancer
Bae, S.-Y., Ling, H.-H., Zhang, J., Chen, Y., Chen, H., Kumar, D., Saw, A., Rai, K., Viny, A., DePinho, R., et al. (2023) · bioRxiv · doi:10.1038/s41556-026-01984-y · Cited by 1
“Together, these results establish MED4 as a key regulator of chromatin organization that restrains ECM remodelling and metastatic niche activation.”
Tulchinsky, M., & Weihs, D. (2023) · Journal of Biomedical Materials Research. Part A · doi:10.1002/jbm.a.37597 · Cited by 1
Speckle rheological spectroscopy reveals wideband viscoelastic spectra of biological tissues
Leartprapun, N., Zeng, Z., Hajjarian, Z., Bossuyt, V., & Nadkarni, S. (2023) · bioRxiv · doi:10.1101/2023.06.08.544037 · Cited by 1
Jak2 and Jaw Muscles Are Required for Buccopharyngeal Membrane Perforation during Mouth Development
Dickinson, A. (2023) · Journal of Developmental Biology · doi:10.3390/jdb11020024 · Cited by 1
“Secondly, actin dynamics were also perturbed by inhibiting Rho-associated kinase (ROCK) which is critical to regulating actin organization [51].”
BackgroundKumar, V., Naqvi, S. M., Verbruggen, A. S. K., McEvoy, E., & McNamara, L. M. (2022) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2022.09.19.508588 · Cited by 2
Higgins, G., Higgins, F., Peres, J., Lang, D. M., Abdalrahman, T., Zaman, M., Prince, S., & Franz, T. (2023) · bioRxiv · doi:10.1101/2022.06.09.495509 · Cited by 1
“Although ECM mechanics and its role in guiding metastasis have received increasing attention [15, 28-31], little is known about the biomechanics of the cell-ECM relationship at distant sites of metastasis and why cells may favour specific distant organs over others.”
BackgroundImplicit implementation of the cell-micropillars interaction during cell drop under gravity
Allena, R., & Aubry, D. (2023) · Mechanics research communications · doi:10.1016/j.mechrescom.2023.104129 · Cited by 1
Garcia-Herreros, A., Yeh, Y.-T., Tu, Y.-P., Kandasamy, A., del Álamo, J. D., & Criado-Hidalgo, E. (2023) · bioRxiv · doi:10.1101/2023.03.31.535168 · Cited by 1
Rubin, M. (2023) · Journal of elasticity · doi:10.1007/s10659-023-09993-w · Cited by 1
“Also, breast tumors [31] and pancreatic tumors [19] were found to be 5-7 times stiffer than the surrounding normal tissue.”
Teplický, T., Gregorová, M., Kalafutová, A., Hanzel, O., Mateašík, A., Filová, B., & Čunderlı́ková, B. (2022) · Biophysical Chemistry · doi:10.1016/j.bpc.2022.106944 · Cited by 2
Hwang, H. W., Kim, S., Hwang, H., Han, H., Jeon, H., Kim, Y.-C., Lee, H., Sun, J., & Ok, M. (2022) · ACS Applied Nano Materials · doi:10.1021/acsanm.2c01936 · Cited by 1
Caballero, D., Lima, A. C., Abreu, C. M., Neves, N., Correlo, V., Oliveira, J., Reis, R., & Kundu, S. (2022) · In vitro models · doi:10.1007/s44164-022-00020-1 · Cited by 1
Mechanically primed cells transfer memory to fibrous matrices for persistent invasionPreprint
Almeida, J. A., Mathur, J., Lee, Y.-L., Sarker, B., & Pathak, A. (2022) · bioRxiv · doi:10.1101/2022.05.02.490316 · Cited by 1
“(ψ) by the past environment and (2) direct mechanosensing (φ) of the current matrix (Fig.”
BackgroundAndersen, T., Wörthmüller, D., Probst, D., Wang, I., Moreau, P., Fitzpatrick, V., Boudou, T., Schwarz, U., & Balland, M. (2022) · bioRxiv · doi:10.1101/2022.03.15.484408 · Cited by 1
“In particular, changes in RhoA-regulation have been connected to the progression of cancer (Paszek et al. 2005; Gulhati et al. 2011).”
BackgroundMechanical instability of a solid inclusion in a soft matrix due to indentation
Liu, S., & Wan, K.-T. (2022) · European Journal of Mechanics - A/Solids · doi:10.1016/j.euromechsol.2021.104474 · Cited by 1
Jerrell, R., Leih, M. J., & Parekh, A. (2021) · Data in Brief · doi:10.1016/j.dib.2021.107684 · Cited by 1
The mechanical force of minority cells modulates the tumor taxol-resistance and progressionPreprint
Zhang, D., Feng, X.-Y., Wang, G.-X., Lu, L., Feng, F., Wang, X.-Y., Yu, C., Chai, Y., Ge, M.-F., & Yao, L. (2021) · Research Square · doi:10.21203/rs.3.rs-948406/v1 · Cited by 1
An Optimized O9-1/Hydrogel System for Studying Mechanical Signals in Neural Crest Cells
Le, T. P., Zhao, X., Erhardt, S., Gu, J.-H., Wang, H., Findley, T. O., & Wang, J. (2021) · Journal of Visualized Experiments · doi:10.3791/62693 · Cited by 1
ECM dimensionality tunes actin tension to modulate the endoplasmic reticulum and spheroid phenotype
Kai, F., Ou, G., Tourdot, R., Stashko, C., Gaietta, G., Swift, M., Volkmann, N., Long, A. F., Han, Y., Huang, H. H., et al. (2021) · bioRxiv · doi:10.1101/2021.07.14.452329 · Cited by 1
Self-citationExtracellular Matrix in Preterm Premature Rupture of Fetal Membranes
Zhong, N. A. (2021) · American Journal of Biomedical Science & Research · doi:10.34297/ajbsr.2021.13.001831 · Cited by 1
“ECM stiffening can also enhance cytoskeletal tension by Rho/ROCK signaling activation and increase cell-ECM adhesion connecting the ECM to the cytoskeleton by local adhesion proteins [59,60].”
BackgroundPressure drives rapid burst-like collective migration from 3D cancer aggregatesPreprint
Raghuraman, S., Schubert, A., Bröker, S., Jurado, A., Müller, A., Brandt, M., Vos, B., Hofemeier, A., Abbasi, F., Stehling, M., et al. (2021) · bioRxiv · doi:10.1101/2021.04.25.441311 · Cited by 1
De, P. S., & De, R. (2021) · bioRxiv · doi:10.1101/2021.04.23.441062 · Cited by 1
Remote control of magnetic nanocomplexes for delivery and destruction of cancer cells
Orel, V., Syvak, L., & Orel, V. (2021) · Journal of Biomaterials Applications · doi:10.1177/08853282211005098 · Cited by 1
“The deformation of MCs disrupts tensional homeostasis at the cellular and tissue levels.(44) Since magnetic anisotropy and shape changes characterize the mechanical deformability of internalized MCs, magnetic fields can provide a remote way of overcoming geometry limitations for targeting.”
BackgroundMatrix Composition Modulates Vitamin D3's Effects on 3D Collagen Fiber Organization by MCF10A Cells
Hasan, N., Zhang, Y., Georgakoudi, I., Sonnenschein, C., & Soto, A. (2021) · Tissue Engineering. Part A · doi:10.1089/ten.tea.2020.0371 · Cited by 1
Pre-metastatic niche drives breast cancer invasion by modulating MSC homing and CAF differentiationPreprint
Saxena, N., Bhardwaj, G., Jadhav, S., Zafar, H., & Sen, S. (2021) · bioRxiv · doi:10.1101/2021.01.12.426460 · Cited by 1
“5 kPa), pre-metastatic tumor stroma (≈ 2 kPa), and metastatic tumor stroma (≈ 5 kPa) [35, 36].”
Szulczewski, J. M., Inman, D. R., Proestaki, M., Notbohm, J., Burkel, B. M., & Ponik, S. M. (2020) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2020.08.12.248179 · Cited by 2
Physics of the Extracellular Matrix and Biology of Tumors — A Close Relationship
Engelke, H. (2020) · Biophysical Reviews and Letters · doi:10.1142/s1793048020300030 · Cited by 2
Urcun, S., Rohan, P., Skalli, W., Nassoy, P., Bordas, S., & Sciumè, G. (2020) · bioRxiv · doi:10.1101/2020.06.09.142927 · Cited by 1
“The initial guess of pcrit have been chosen according to the work of Helmlinger et al. (1997) and Paszek et al. (2005), and the value of p1 has been set by observation of the experimental data.”
Tjoa, H., Mei, L., Silva, H. D., Tong, D. C., & Guan, G.-Z. (2026) · Journal of the Royal Society of New Zealand · doi:10.1002/snz2.70090
“…apparent Young ’ s modulus under defined in vitro conditions, tumour tissues may become mechanically stiffer through ECM remodelling, increased collagen deposition and crosslinking, stromal activation and altered tissue architecture (Butcher et al. 2009; Levental et al. 2009; Paszek et al. 2005).”
Budhwani, B. M. K., Budhwani, K. K. K., Guenter, R., Patel, V. M., Rupani, A. A., Rose, J., & Budhwani, K. (2026) · Biomedicines · doi:10.3390/biomedicines14112421
Barash, I. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1982804
Endocrine Signaling and Tissue Remodeling in Gynecomastia: Implications for Treatment Response
Deng, J., Tong, S., Liu, S., Zhou, H., & Ren, M. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27219443
Shear-lag mechanics of adhesive bias in durotaxis and viscotaxis
Stefano, S. D., & Lucci, G. (2026) · Meccanica (Milano. Print) · doi:10.1007/s11012-026-02177-5
“Changes in tissue stiffness are for instance associated with tumour progression [1] and fibrosis [2].”
High-content morphological profiling by Cell Painting in 3D spheroids
Ringers, C., Holmberg, D., Larsson, A., Jung, B., Jarvius, M., Łuchniak, A., Rosén, D., Johansson, M., Georgiev, P., Seashore-Ludlow, B. A., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-78596-5 · Cited by 7
“The rigid 2D surface of a fl ask, on the other hand, directs cells to form large focal adhesions instead of engaging in 3D interactions 21,23,24 .”
Hanselmann, R. G. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1936518
Glycoconjugates tune the viscoelastic signature of mammary tumor progressionPreprint
Sharma, A., Baude, J. A., Papez, M., Gionet-Gonzales, M. A., & Stowers, R. S. (2026) · bioRxiv · doi:10.64898/2026.10.20.760544
“Furthermore, reducing the expression of proteoglycans, mucin 1, and aberrant protein glycosylation can prevent breast cancer cell invasion stiffness can drive a malignant phenotype in vitro 3,21,44,81–85 .”
Wang, T., & Xiao, Q. (2026) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2026.1936991
Ayyalasomayajula, S. S., Morton, J. P., Berry, C., & Walker, M. (2026) · bioRxiv · doi:10.64898/2026.10.15.759386
Varinská, L., & Koolwijk, P. (2026) · Pharmacological Reports · doi:10.1007/s43440-026-00912-z
Jain, K., Thakar, D., Parihar, K., Lin, J. J. Y., Hayward, M.-K., Musiime, M., Lakins, J. N., Hansen, S. D., Radhakrishnan, R., Groves, J. T., et al. (2026) · bioRxiv · doi:10.64898/2026.10.06.757133
“Consistent with this, RTKs including Eph receptors [52-54] and EGFR [7, 8, 55] exhibit sensitivity to ECM stiffness and actomyosin contractility, although whether effects are”
InfluentialSelf-citationMultiscale mechanobiology of circulating tumor cells: microfluidics and atomic force microscopy
Glia, A., Deliorman, M., & Qasaimeh, M. (2026) · Frontiers in Lab on a Chip Technologies · doi:10.3389/frlct.2026.1968871
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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