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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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Pascucci, A., Karim, S., Morton, J. P., Vassalli, M., & Walker, M. (2026) · Mechanobiology · doi:10.1177/29780241261450044
“12 Several molecular players associated with cell contractility have been implicated in PDAC; for instance, focal adhesion kinase, inhibition of which increases PDAC receptiveness to immunotherapy.”
Zheng, L., Zhang, F., Xu, J., Wu, Y., Zhong, S., Xie, G., Ji, B., Lü, D., & Long, M. (2026) · Acta Biomaterialia · doi:10.1016/j.actbio.2026.05.022
Ichise, S. F., Taga, Y., Fujita, K., & Koide, T. (2026) · bioRxiv · doi:10.64898/2026.04.21.720034
“The stiffness of the peritumoral matrix is not only clinically associated with poor prognosis[3,4] but also has been reported to be a factor driving malignant phenotypes in in vitro models and in transplantation studies using mice [5–7].”
Platz-Baudin, E., Eschenbruch, J., Herfs, Y., Dreissen, G., Wein, R., van der Vorst, E. P. C., Rose, M., Merkel, R., & Noetzel, E. (2026) · bioRxiv · doi:10.64898/2026.04.15.717430
“These results show that HRas hyperactivation alone induced an invasive transition in originally non-transformed breast epithelial spheroids, even under microenvironmental conditions that reflect the compliance of healthy breast tissue 37, 38 .”
Sokolov, I. (2026) · Japanese Journal of Applied Physics · doi:10.35848/1347-4065/ae5a43
Hu, Z., Majeski, H. E., Mestre‐Farrera, A., Cai, S., Lalezarzadeh, A., Zhang, Y., Arimoto, K., Zhang, D., Piwnica-Worms, H. M., Fattet, L., et al. (2026) · Nature Communications · doi:10.1038/s41467-026-70518-9 · Cited by 1
“…cells, which are known to express a gene signature enriched with the Epithelial-Mesenchymal Transition (EMT) program, undergo EMT and invade surrounding matrices when cultured at tissue stiffnesses between 1000 – 5700 Pascals (Pa), which were detected in some human breast tumors 8 – 10 , 23 .”
Quantifying single-cell responses to irradiation in 3D
François, J., Simerzin, A., Jambhekar, A., & Lahav, G. (2026) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2026.1735308
“Since protein dynamics in 3D-embedded multicellular structures can be influenced by signaling from both cell-ECM and cell-cell interactions, we next examined the p21 response in spheroids (Paszek et al., 2005; Helmlinger et al., 1997; Kapałczyńska et al., 2016).”
Cofré, J. (2026) · arXiv (Cornell University) · doi:10.48550/arxiv.2603.18293
“Surprisingly, both cancer (Paszek and Weaver 2004; Paszek et al. 2005; DuFort et al. 2011) and embryogenesis (gastrulation in particular) (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.”
Matrix stress relaxation promotes glioblastoma cell migration in a ligand-specific manner
Żochowski, K., Szczepanek-Dulska, M., Zakrzewska, M., Sawieljew, M., Piktel, E., Bucki, R., & Pogoda, K. (2026) · Scientific Reports · doi:10.1038/s41598-026-43432-9
“Under conditions of increased rigidity or elasticity, effective activation of the integrin-FAK-Rho/ROCK pathway may lead to more elongated morphology, stronger actomyosin tension, and longer straight-line movement segments 4,46 .”
Sharma, R. K., Kramer, M., Hough, K., Vessels, T., Canturk, L., Wang, H., Ashton, R., Sewell-Loftin, M., Goliwas, K., Deshane, J., et al. (2026) · International Journal of Molecular Sciences · doi:10.3390/ijms27052456
“Reduced MUC5AC reflects loss of epithelial differentiation consistent with EMT and invasion [42].”
A 3D Collagen-Based In Vitro Cancer Model Created Through Modular Tissue Engineering
Baghbadorani, N. D., Bosso, M., Greene, R., Dzikowski, T., Bevelander, B. B., Gagnon, A., Johannson, M., Javan, M., Soori, P., & Chamberlain, M. D. (2026) · Cancers · doi:10.3390/cancers18060935
“This likely reflects a normalization of the cells’ phenotype, where the physiological stiffness of the 3D matrix mitigates the artificial mesenchymal activation typically induced by rigid 2D culture plastic [54,55].”
Lu, Y., Podobnik, M., Ando, K., Pan, M., Locop, J., Guo, A., Mourrain, P., Kikuchi, K., Ruparelia, A. A., & Currie, P. D. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.02.23.707519 · Cited by 1
“Under certain pathological conditions, such negative feedback could be disrupted 53-56 , though this contributes to additional complexity to the functional validation.”
Hydrogel-imposed boundary conditions guide single-lumen neuroepithelial morphogenesisPreprint
Huang, M. S., Roth, J. G., Kim, D., Pashin, K. P., Pizzarella, D., Yang, T. M., Liu, Y., Navarro, R. S., Palmer, T. D., & Heilshorn, S. C. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.30.702717 · Cited by 1
“While the idea of tensional homeostasis originated from studies in cancer biology, 79 this concept has not been as explored in a developmental context.”
From confinement to remodeling: modeling topotaxis-driven cell migration in obstacles networks
Allena, R. (2026) · Journal of Mathematical Biology · doi:10.1007/s00285-026-02345-x
“In stiffer microenvironments, increased focal adhesion maturation promotes the development of invadopodia and improves cell traction leading to more invasive phenotypes (Alexander et al. 2008; Paszek et al. 2005).”
Coaxial bioprinting of microsphere bioink to engineer heterogeneous vascularized lung cancer model
Gao, Q., Guo, Z., Zhang, S., Xia, J., Li, J., Yuan, T., Chen, J., Fang, Y., Qiu, J., & Wei, R. (2026) · Biomaterials Advances · doi:10.1016/j.bioadv.2026.214741 · Cited by 1
Collagen type I promotes pancreatic tumor growth and limits immune cell infiltrationPreprint
Thorseth, M., Johansen, A. Z., Baker, K. J., Carretta, M., Rømer, A. M. A., Jensen, C., Jürgensen, H. J., Linder, H., Czajkowski, N. K., Kuczek, D. E., et al. (2026) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.64898/2026.01.09.698616
“Furthermore, high-density Col1 matrices have been shown to promote malignant transformation, stimulate epithelial-to-mesenchymal transition (EMT), and enhance cancer cell invasion and migration in vitro 26,31 .”
Lin, W., Sun, M., Huang, K. N., & Li, H. (2026) · Biosurface and Biotribology · doi:10.1049/bsb2.70023
Moroishi, K., Hermodsson, T., Greiff, L., Lindstedt, M., & Matsusaki, M. (2025) · bioRxiv · doi:10.64898/2025.12.22.696030
Sauer, F., Jordan, J., Meyer, T., de Moraes, P. A. D., Flé, G., Käs, J., & Sack, I. (2025) · bioRxiv · doi:10.64898/2025.12.16.694603
“Various types of collagen networks are accessible for experiments in small volumes covering stiffness ranges similar to those of biological soft-tissue environments (4–6).”
Cohen, D., Lázaro‐Diéguez, F., & Müsch, A. (2025) · Journal of Cell Science · doi:10.1242/jcs.264412
“…0.6 mg/ml, which we used as overlay gel, likely has a Young ’ s modulus of Elasticity, a material property measuring stiffness, at or below 1 kPa (Paszek et al., 2005; Raub et al., 2010), whereas 0.5% agarose is estimated to raise the Young ’ s modulus of the overlay gel by a magnitude or more…”
InfluentialStiffness-mediated paracrine signaling enhances induction of EMT in oral squamous cell carcinoma
Moon, S. Y., Lamers, M. L., & Engler, A. J. (2025) · APL Bioengineering · doi:10.1063/5.0299456
Wang, R., Zhang, W.-S., Li, X., Wang, H., Ji, Y.-N., Zhao, J., Song, J.-X., & Yi, Z.-Q. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1662599
A tale of two distinct actin networks underlies the entire life cycle of focal adhesionPreprint
Dong, R., Ishii, K., Plotnikov, S. V., & Liu, J. (2025) · bioRxiv · doi:10.1101/2025.11.12.688129
“…of the cell, FA adapts the cell’s traction force according to the mechanics of the local ECM to mediate directed cell migrations ( e.g. , durotaxis (5-7)), which are crucial for many physiological processes such as development (8, 9), tissue formation (10, 11), and cancer metastasis (12-14).”
How to stop worrying about model microfoundationality: lessons from multiscale cancer modeling
Neal, J. P. (2025) · Synthese · doi:10.1007/s11229-025-05344-5
Glutamine metabolism drives B cell proliferation under elevated atmospheric pressure
Maeda, A., Nita, A., & Moroishi, T. (2025) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2025.152892
Amoeboid-Mesenchymal Transition and the Proteolytic Control of Cancer Invasion Plasticity
Olson, A. W., Li, J., Li, X.-Y., King, L., Banerjee, K., McCoy, A. J., Gondal, M., Chinnaiyan, A., El-Ashry, D., Keller, E. T., et al. (2025) · bioRxiv · doi:10.1101/2025.10.24.684403
Visonà, A., Soulan, S., Diény, B., Morel, R., & Nicolas, A. (2025) · bioRxiv · doi:10.1101/2025.10.15.682498
“These findings support the idea that vibrating MDs alter cell contractility, a primary marker of cell fate, consistent with numerous studies correlating cell contractility levels with proliferation or migration capabilities [70–72].”
A microfluidic rheometer for tumor mechanics and invasion studies
Suh, Y. J., Liu, M., Zhu, B., Pandey, M., Cheung, B. C. H., Kim, J., Bouklas, N., Roh, C., Segall, J. E., Hui, C., et al. (2025) · Lab on a Chip · doi:10.1039/d5lc00504c · Cited by 2
Protocol to culture cells on genipin-mixed collagen gels with different stiffnesses
Ishihara, S., & Haga, H. (2025) · STAR Protocols · doi:10.1016/j.xpro.2025.104125
“2,9 These methods are convenient, however, the exact concentration of collagen in these substrates cannot be controlled.”
Terrassoux, L., Hazard, C., Laratte, A., Balsamelli, J., Arcicasa, M., Fong, E. L. S., Baland, L., Soncin, F., Cappello, G., Maurage, C., et al. (2025) · Small · doi:10.1002/smll.202505343 · Cited by 2
Nuclear destabilisation – a possible genesis of cancer?
Scott, D., Bettariga, F., Ventin, M., Bishop, C. J., & Stordal, B. (2025) · Biological reviews/Biological reviews of the Cambridge Philosophical Society · doi:10.1111/brv.70052
“Indeed, within mammary tissue, tumour tissue is around 24 times stiffer (mean ± SEM 167 ± 31 versus 4049 ± 938 Pa; Paszek et al ., 2005), yet cancer cells maintain their compromised mechanical pro fi le (Massey et al ., 2024).”
Mechanical factors in the breast cancer microenvironment: Emphasizing functional adaptation.
Ray, S., & Mukherjee, S. (2025) · Biochemical and Biophysical Research Communications - BBRC · doi:10.1016/j.bbrc.2025.152048
Pimenta, R. M., Skon-Hegg, C., Rose-Hellekant, T., & Holy, J. (2025) · Acta Histochemica · doi:10.1016/j.acthis.2025.152238
Wearable Nanoelectronic Devices for Skin Wound Healing
Liu, Y., Jia, Z., Huang, Y., Gao, Y., Yang, L., & Zhang, D. (2025) · Journal of Nanoelectronics and Optoelectronics · doi:10.1166/jno.2025.3709
De, P. S., & De, R. (2024) · Physical Review E · doi:10.1103/physreve.110.054414
Bridging the Gap in Cancer Cell Behavior Against Matrix Stiffening: Insights from a Trizonal ModelPreprint
Torki, M. E., Liu, F., Xu, R., Chen, Y., Fredberg, J., & Chen, Z. (2023) · bioRxiv (Cold Spring Harbor Laboratory) · doi:10.1101/2023.12.02.569730
Editorial overview: Navigating the landscapes of mechanobiology and cell-cell interactions.
Strömblad, S., & Fujita, Y. (2024) · Current Opinion in Cell Biology · doi:10.1016/j.ceb.2024.102353
Shen, B., & Zhang, Y.-X. (2024) · Physical Review E · doi:10.1103/physreve.111.014417
Assoian, R., Xu, T., & Roberts, E. (2023) · bioRxiv · doi:10.1101/2023.11.15.567271
Breast Cancer Risk Estimation Using Patient Health Information and Tactile Sensing System
Choi, S., Caroline, D., & Won, C.-H. (2023) · Italian National Conference on Sensors · doi:10.1109/sensors56945.2023.10324953
“It shows that the malignant tumor is stiffer than the other tissues, as stated in [22] and [23].”
BackgroundSurface wave elastography measurements on tissue-mimicking phantoms
Singh, A., Verma, M., & John, R. (2023) · Optics and Photonics International Conference · doi:10.1117/12.3007510
Wagle, M. M., Rao, A. K., Kabekkodu, S. P., & Mallya, S. P. (2023) · Asian Pacific Journal of Cancer Prevention · doi:10.31557/apjcp.2023.24.5.1601
“Since tumor cells continuously interact with ECM, an increased disruption can accelerate tumor progression by negatively interfering with cell adhesion (Fang et al., 2014; Paszek et al., 2005; Xu et al., 2019).”
BackgroundMeasuring pico-Newton Forces with Lipid Anchors as Force Sensors in Molecular Dynamics Simulations
Kav, B., Weikl, T. R., & Schneck, E. (2023) · The Journal of Physical Chemistry B · doi:10.1021/acs.jpcb.3c00063
Tissue-engineered models of lung cancer premalignancyPreprint
Blomberg, R., Sompel, K., Hauer, C., Peña, B., Driscoll, J., Hume, P., Merrick, D., Tennis, M., & Magin, C. M. (2023) · bioRxiv · doi:10.1101/2023.03.15.532835
Cruz-Acuña, R., Kariuki, S. W., Sugiura, K., Loebel, C., Karakasheva, T. A., Gabre, J., Burdick, J., & Rustgi, A. (2022) · bioRxiv · doi:10.1101/2022.11.13.516357
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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