The DOI matches its Crossref record; 3 of the 3 references it cites were found in a registry or an index.
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.
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“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]
Citations
Cites
Effects of substrate stiffness on cell morphology, cytoskeletal structure, and adhesion
Yeung, T., Georges, P. C., Flanagan, L. A., Marg, B., Ortiz, M., Funaki, M., Zahir, N., Ming, W., Weaver, V., & Janmey, P. A. (2005) · Cell Motility and the Cytoskeleton · doi:10.1002/cm.20041 · Cited by 2,325
Self-citationMyotubes differentiate optimally on substrates with tissue-like stiffness
Engler, A. J., Griffin, M. A., Sen, S., Bönnemann, C. G., Sweeney, H. L., & Discher, D. E. (2004) · The Journal of Cell Biology · doi:10.1083/jcb.200405004 · Cited by 1,743
Cancer cells compress intratumour vessels
Padera, T. P., Stoll, B. R., Tooredman, J. B., Capen, D., Tomaso, E. D., & Jain, R. K. (2004) · Nature · doi:10.1038/427695a · Cited by 857
Flagged first, then by citations
Research works printed but not linked: 48
- Akiri, 2003, Lysyl oxidase-related protein-1 promotes tumor fibrosis and tumor progression in vivo, Cancer Res., 63, 1657
- Arias-Salgado, 2003, Src kinase activation by direct interaction with the integrin β cytoplasmic domain, Proc. Natl. Acad. Sci. USA, 100, 13298, 10.1073/pnas.2336149100 · DOI
- Azar, 2001, A deformable finite element model of the breast for predicting mechanical deformations under external perturbations, Acad. Radiol., 8, 965, 10.1016/S1076-6332(03)80640-2 · DOI
- Beil, 2003, Sphingosylphosphorylcholine regulates keratin network architecture and visco-elastic properties of human cancer cells, Nat. Cell Biol., 5, 803, 10.1038/ncb1037 · DOI
- Bershadsky, 2003, Adhesion-dependent cell mechanosensitivity, Annu. Rev. Cell Dev. Biol., 19, 677, 10.1146/annurev.cellbio.19.111301.153011 · DOI
- Burridge, 2004, Rho and Rac take center stage, Cell, 116, 167, 10.1016/S0092-8674(04)00003-0 · DOI
- Chrzanowska-Wodnicka, 1996, Rho-stimulated contractility drives the formation of stress fibers and focal adhesions, J. Cell Biol., 133, 1403, 10.1083/jcb.133.6.1403 · DOI
- Colpaert, 2001, The presence of a fibrotic focus is an independent predictor of early metastasis in lymph node-negative breast cancer patients, Am. J. Surg. Pathol., 25, 1557, 10.1097/00000478-200112000-00016 · DOI
- Croft, 2004, Conditional ROCK activation in vivo induces tumor cell dissemination and angiogenesis, Cancer Res., 64, 8994, 10.1158/0008-5472.CAN-04-2052 · DOI
- Debnath, 2003, Morphogenesis and oncogenesis of MCF-10A mammary epithelial acini grown in three-dimensional basement membrane cultures, Methods, 30, 256, 10.1016/S1046-2023(03)00032-X · DOI
- Delcommenne, 1995, Control of integrin expression by extracellular matrix, J. Biol. Chem., 270, 26794, 10.1074/jbc.270.45.26794 · DOI
- Fritz, 1999, Rho GTPases are over-expressed in human tumors, Int. J. Cancer, 81, 682, 10.1002/(SICI)1097-0215(19990531)81:5<682::AID-IJC2>3.0.CO;2-B · DOI
- Galbraith, 2002, The relationship between force and focal complex development, J. Cell Biol., 159, 695, 10.1083/jcb.200204153 · DOI · Paper page
- Gefen, 2003, Age-dependent changes in material properties of the brain and braincase of the rat, J. Neurotrauma, 20, 1163, 10.1089/089771503770802853 · DOI
- Guo, 2004, Integrin signalling during tumour progression, Nat. Rev. Mol. Cell Biol., 5, 816, 10.1038/nrm1490 · DOI
- Huang, 2004, Cell mechanics and mechanotransduction: pathways, probes, and physiology, Am. J. Physiol. Cell Physiol., 287, 1, 10.1152/ajpcell.00559.2003 · DOI
- Keller, 2003, How we are shaped: the biomechanics of gastrulation, Differentiation, 71, 171, 10.1046/j.1432-0436.2003.710301.x · DOI
- Khaled, 2004, Palpation imaging using a haptic system for virtual reality applications in medicine, Stud. Health Technol. Inform., 98, 147
- Lark, A.L., Livasy, C.A., Dressler, L., Moore, D.T., Millikan, R.C., Geradts, J., Iacocca, M., Cowan, D., Little, D., Craven, R.J., and Cance, W. (2005). High focal adhesion kinase expression in invasive breast carcinomas is associated with an aggressive phenotype. Mod Pathol., in press. Published online April 29, 2005. 10.1038/modpathol.3800424. · DOI
- Lee, 2004, Mitogenic signal transduction by integrin- and growth factor receptor-mediated pathways, Mol. Cells, 17, 188, 10.1016/S1016-8478(23)13026-3 · DOI
- Li, 2003, Activation of integrin αIIbβ3 by modulation of transmembrane helix associations, Science, 300, 795, 10.1126/science.1079441 · DOI
- Liu, 2004, Polarity and proliferation are controlled by distinct signaling pathways downstream of PI3-kinase in breast epithelial tumor cells, J. Cell Biol., 164, 603, 10.1083/jcb.200306090 · DOI
- Lo, 2000, Cell movement is guided by the rigidity of the substrate, Biophys. J., 79, 144, 10.1016/S0006-3495(00)76279-5 · DOI · Paper page
- Luo, 2004, Locking the β3 integrin I-like domain into high and low affinity conformations with disulfides, J. Biol. Chem., 279, 10215, 10.1074/jbc.M312732200 · DOI
- Luo, 2005, Disrupting integrin transmembrane domain heterodimerization increases ligand binding affinity, not valency or clustering, Proc. Natl. Acad. Sci. USA, 102, 3679, 10.1073/pnas.0409440102 · DOI
- McLean, 2004, Specific deletion of focal adhesion kinase suppresses tumor formation and blocks malignant progression, Genes Dev., 18, 2998, 10.1101/gad.316304 · DOI
- Moore, 2002, Control of embryonic lung branching morphogenesis by the Rho activator, cytotoxic necrotizing factor 1, J. Surg. Res., 104, 95, 10.1006/jsre.2002.6418 · DOI
- Netti, 2000, Role of extracellular matrix assembly in interstitial transport in solid tumors, Cancer Res., 60, 2497
- Nicolas, 2004, Cell mechanosensitivity controls the anisotropy of focal adhesions, Proc. Natl. Acad. Sci. USA, 101, 12520, 10.1073/pnas.0403539101 · DOI
- O’Brien, 2001, Rac1 orientates epithelial apical polarity through effects on basolateral laminin assembly, Nat. Cell Biol., 3, 831, 10.1038/ncb0901-831 · DOI
- O’Brien, 2002, Opinion: Building epithelial architecture: insights from three-dimensional culture models, Nat. Rev. Mol. Cell Biol., 3, 531, 10.1038/nrm859 · DOI · Paper page
- Paszek, 2004, The tension mounts: mechanics meets morphogenesis and malignancy, J. Mammary Gland Biol. Neoplasia, 9, 325, 10.1007/s10911-004-1404-x · DOI
- Reinhart-King, 2003, Endothelial cell traction forces on RGD-derivatized polyacrylamide substrata, Langmuir, 19, 1573, 10.1021/la026142j · DOI
- Riveline, 2001, Focal contacts as mechanosensors: externally applied local mechanical force induces growth of focal contacts by an mDia1-dependent and ROCK-independent mechanism, J. Cell Biol., 153, 1175, 10.1083/jcb.153.6.1175 · DOI
- Roovers, 2003, Effects of rho kinase and actin stress fibers on sustained extracellular signal-regulated kinase activity and activation of G(1) phase cyclin-dependent kinases, Mol. Cell. Biol., 23, 4283, 10.1128/MCB.23.12.4283-4294.2003 · DOI
- Sahai, 2002, ROCK and Dia have opposing effects on adherens junctions downstream of Rho, Nat. Cell Biol., 4, 408, 10.1038/ncb796 · DOI
- Sahai, 2001, Cross-talk between Ras and Rho signalling pathways in transformation favours proliferation and increased motility, EMBO J., 20, 755, 10.1093/emboj/20.4.755 · DOI
- Shi, 2003, A novel mode for integrin-mediated signaling: tethering is required for phosphorylation of FAK Y397, Mol. Biol. Cell, 14, 4306, 10.1091/mbc.E03-01-0046 · DOI
- Tzima, 2001, Activation of integrins in endothelial cells by fluid shear stress mediates Rho-dependent cytoskeletal alignment, EMBO J., 20, 4639, 10.1093/emboj/20.17.4639 · DOI
- Vial, 2003, ERK-MAPK signaling coordinately regulates activity of Rac1 and RhoA for tumor cell motility, Cancer Cell, 4, 67, 10.1016/S1535-6108(03)00162-4 · DOI
- Wang, 1998, Reciprocal interactions between β1-integrin and epidermal growth factor receptor in three-dimensional basement membrane breast cultures: a different perspective in epithelial biology, Proc. Natl. Acad. Sci. USA, 95, 14821, 10.1073/pnas.95.25.14821 · DOI · Paper page
- Wang, 2000, Substrate flexibility regulates growth and apoptosis of normal but not transformed cells, Am. J. Physiol. Cell Physiol., 279, C1345, 10.1152/ajpcell.2000.279.5.C1345 · DOI
- Weaver, 2002, β4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium, Cancer Cell, 2, 205, 10.1016/S1535-6108(02)00125-3 · DOI
- White, 2004, Targeted disruption of β1-integrin in a transgenic mouse model of human breast cancer reveals an essential role in mammary tumor induction, Cancer Cell, 6, 159, 10.1016/j.ccr.2004.06.025 · DOI · Paper page
- Wozniak, 2003, ROCK-generated contractility regulates breast epithelial cell differentiation in response to the physical properties of a three-dimensional collagen matrix, J. Cell Biol., 163, 583, 10.1083/jcb.200305010 · DOI
- Zahir, 2003, Autocrine laminin-5 ligates α6β4 integrin and activates RAC and NFκB to mediate anchorage-independent survival of mammary tumors, J. Cell Biol., 163, 1397, 10.1083/jcb.200302023 · DOI
- Zajaczkowski, 2003, Cell-matrix adhesions on poly(vinyl alcohol) hydrogels, Tissue Eng., 9, 525, 10.1089/107632703322066705 · DOI
- Zhong, 1997, Rho-stimulated contractility contributes to the fibroblastic phenotype of Ras-transformed epithelial cells, Mol. Biol. Cell, 8, 2329, 10.1091/mbc.8.11.2329 · DOI
Cited by
Sorted by citations
Items 101–200 of 1,121
Immune Modulatory Properties of Collagen in Cancer
Rømer, A. M. A., Thorseth, M., & Madsen, D. H. (2021) · Frontiers in Immunology · doi:10.3389/fimmu.2021.791453 · Cited by 237
“This in turn activates signaling pathways, increases cytoskeletal tension and further FA formation, promoting malignant transformation (53).”
BackgroundLinking cell mechanical memory and cancer metastasis
Cambria, E., Coughlin, M. F., Floryan, M. A., Offeddu, G. S., Shelton, S. E., & Kamm, R. D. (2024) · Nature reviews. Cancer · doi:10.1038/s41568-023-00656-5 · Cited by 204
“…force generation by tumour cells in response to high ECM stiffness is driven by integrin clustering and signalling through EGFR, which activates extracellular signal-regulated kinase 1/2 (ERK1/2) and increases RHO–Rho-associated kinase (ROCK)- mediated actomyosin contractility 25,108 .”
InfluentialFrom Structure to Phenotype: Impact of Collagen Alterations on Human Health
Arseni, L., Lombardi, A., & Orioli, D. (2018) · International Journal of Molecular Sciences · doi:10.3390/ijms19051407 · Cited by 186
“Tissue stiffness can drive malignant transformation via integrin-mediated mechanisms [23] and such fibrotic “stiff” lesions are associated with a poor prognosis [24].”
BackgroundMatrix Stiffness Contributes to Cancer Progression by Regulating Transcription Factors
Ishihara, S., & Haga, H. (2022) · Cancers · doi:10.3390/cancers14041049 · Cited by 220
“Another study reported that culturing epithelial cells on a stiff matrix mimicking tumor tissues elevated cytoskeletal tension, which perturbs tissue polarity, increases growth, and disrupts normal lumen formation, resembling tumor initiation [1].”
BackgroundGilkes, D. M., Xiang, L., Lee, S. J., Chaturvedi, P., Hubbi, M. E., Wirtz, D., & Semenza, G. L. (2014) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1321510111 · Cited by 184
RetractedNeufeld, L., Yeini, E., Reisman, N., Shtilerman, Y., Ben‐Shushan, D., Pozzi, S., Madi, A., Tiram, G., Eldar‐Boock, A., Ferber, S., et al. (2021) · Science Advances · doi:10.1126/sciadv.abi9119 · Cited by 204
Nanoformulations for combination or cascade anticancer therapy
Miao, L., Guo, S., Lin, C. M., Liu, Q., & Huang, L. (2017) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2017.06.003 · Cited by 178
Cancer chemotherapy resistance: Mechanisms and recent breakthrough in targeted drug delivery
Davodabadi, F., Sajjadi, S. F., Sarhadi, M., Mirghasemi, S., Hazaveh, M. N., Khosravi, S., Andani, M. K., Cordani, M., Basiri, M., & Ghavami, S. (2023) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2023.176013 · Cited by 202
Previtera, M. L., & Sengupta, A. (2015) · PLOS ONE · doi:10.1371/journal.pone.0145813 · Cited by 176
Carey, S. P., Starchenko, A., McGregor, A. L., & Reinhart-King, C. A. (2013) · Clinical & Experimental Metastasis · doi:10.1007/s10585-013-9565-x · Cited by 174
Self-citation3D scaffolds in breast cancer research
Rijal, G., & Li, W. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2015.12.016 · Cited by 169
Xie, W., Wei, X., Kang, H., Jiang, H., Chu, Z., Lin, Y., Hou, Y., & Wei, Q. (2023) · Advanced Science · doi:10.1002/advs.202204594 · Cited by 189
ECM stiffness-tuned exosomes drive breast cancer motility through thrombospondin-1
Patwardhan, S., Mahadik, P., Shetty, O. A., & Sen, S. (2021) · Biomaterials · doi:10.1016/j.biomaterials.2021.121185 · Cited by 183
Implant Fibrosis and the Underappreciated Role of Myofibroblasts in the Foreign Body Reaction
Noskovicova, N., Hinz, B., & Pakshir, P. (2021) · Cells · doi:10.3390/cells10071794 · Cited by 184
Mechanical properties of human tumour tissues and their implications for cancer development
Massey, A. E., Stewart, J. M., Smith, C., Parvini, C. H., McCormick, M., Do, K., & Cartagena‐Rivera, A. X. (2024) · Nature Reviews Physics · doi:10.1038/s42254-024-00707-2 · Cited by 166
“Interestingly, other studies have shown an apparent increase in cortical tension in human melanoma and breast cancer cells owing to upregulation of ERK and Rho signalling substantially increasing actin cytoskeleton tension 12,87 .”
Unger, C., Kramer, N., Walzl, A., Scherzer, M., Hengstschläger, M., & Dolznig, H. (2014) · Advanced Drug Delivery Reviews · doi:10.1016/j.addr.2014.10.015 · Cited by 158
The hallmarks of cancer are also the hallmarks of wound healing
MacCarthy‐Morrogh, L., & Martin, P. B. (2020) · Science Signaling · doi:10.1126/scisignal.aay8690 · Cited by 181
“A cross-linked, stiff matrix encourages integrin clustering and sustained phosphoinositide 3-kinase–Akt and ERK signaling, which promotes both survival and migration, and provides tracks to facilitate invasion away from the primary tumor site (142, 143).”
BackgroundThree-dimensional biomimetic model to reconstitute sprouting lymphangiogenesis in vitro
Kim, S., Chung, M., & Jeon, N. L. (2016) · Biomaterials · doi:10.1016/j.biomaterials.2015.11.019 · Cited by 157
Integrin signaling in cancer: bidirectional mechanisms and therapeutic opportunities
Li, S., Sampson, C., Liu, C., Piao, H., & Liu, H. (2023) · Cell Communication and Signaling · doi:10.1186/s12964-023-01264-4 · Cited by 171
3D bioprinting: improving in vitro models of metastasis with heterogeneous tumor microenvironments
Albritton, J. L., & Miller, J. S. (2017) · Disease Models & Mechanisms · doi:10.1242/dmm.025049 · Cited by 154
Friend or foe? The elusive role of hepatic stellate cells in liver cancer
Cogliati, B., Yashaswini, C. N., Wang, S., Sia, D., & Friedman, S. L. (2023) · Nature Reviews Gastroenterology & Hepatology · doi:10.1038/s41575-023-00821-z · Cited by 159
“Stiff substrates activate integrins 158 , FAK 159 , SRC family kinases 160 and YAP–TAZ 161 signalling, which in turn promote the expression of pro-proliferative and pro-migratory genes in both cancer cells and stromal cells 162 .”
BackgroundNoskovičová, N., Schuster, R., van Putten, S., Ezzo, M., Koehler, A., Boo, S., Coelho, N. M., Griggs, D. W., Ruminski, P., McCulloch, C. A., et al. (2021) · Nature Biomedical Engineering · doi:10.1038/s41551-021-00722-z · Cited by 180
Calvo, F., Ranftl, R., Hooper, S., Farrugia, A. J., Moeendarbary, E., Bruckbauer, A., Batista, F., Charras, G., & Sahai, E. (2015) · Cell Reports · doi:10.1016/j.celrep.2015.11.052 · Cited by 142
Extracellular Matrix Cues Regulate Mechanosensing and Mechanotransduction of Cancer Cells
Mierke, C. T. (2024) · Cells · doi:10.3390/cells13010096 · Cited by 146
The epithelial-mesenchymal transition and the cytoskeleton in bioengineered systems
Leggett, S. E., Hruska, A. M., Guo, M., & Wong, I. Y. (2021) · Cell Communication and Signaling · doi:10.1186/s12964-021-00713-2 · Cited by 190
Sculpting Organs: Mechanical Regulation of Tissue Development
Nelson, C. M., & Gleghorn, J. P. (2012) · Annual Review of Biomedical Engineering · doi:10.1146/annurev-bioeng-071811-150043 · Cited by 130
Perez, V. M., Kearney, J. F., & Yeh, J. J. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.751311 · Cited by 143
Buchanan, C. F., Voigt, E. E., Szot, C. S., Freeman, J. W., Vlachos, P. P., & Rylander, M. N. (2014) · Tissue Engineering Part C: Methods · doi:10.1089/ten.tec.2012.0731 · Cited by 143
Antibody‐Modified Reduced Graphene Oxide Films with Extreme Sensitivity to Circulating Tumor Cells
Li, Y., Lu, Q., Liu, H., Wang, J., Zhang, P., Liang, H., Jiang, L., & Wang, S. (2015) · Advanced Materials · doi:10.1002/adma.201502615 · Cited by 143
Roig‐Rosello, E., & Rousselle, P. (2020) · Biomolecules · doi:10.3390/biom10121607 · Cited by 172
“In a process called “mechanoreciprocity” [119], this increased contractility generates counter-balancing cellular tension in an attempt to balance internal and external forces [120,121].”
BackgroundTissue mechanics in stem cell fate, development, and cancer
Hayward, M.-K., Muncie, J. M., & Weaver, V. M. (2021) · Developmental Cell · doi:10.1016/j.devcel.2021.05.011 · Cited by 159
Self-citationEvolution of cellular morpho-phenotypes in cancer metastasis.
Wu, P.-H., Phillip, J. M., Khatau, S. B., Chen, W.-C., Stirman, J., Rosseel, S., Tschudi, K., Van Patten, J., Wong, M., Gupta, S., et al. (2015) · Scientific Reports · doi:10.1038/srep18437 · Cited by 117
Breast Cancer Cell Invasion into a Three Dimensional Tumor-Stroma Microenvironment
Truong, D., Puleo, J., Llave, A., Mouneimne, G., Kamm, R. D., & Nikkhah, M. (2016) · Scientific Reports · doi:10.1038/srep34094 · Cited by 135
Bauer, J., Emon, M. A. B., Staudacher, J. J., Thomas, A. L., Zessner-Spitzenberg, J., Mancinelli, G., Krett, N., Saif, M. T., & Jung, B. (2020) · Scientific Reports · doi:10.1038/s41598-019-55687-6 · Cited by 133
Rodenhizer, D., Gaude, E., Cojocari, D., Mahadevan, R., Frezza, C., Wouters, B. G., & McGuigan, A. P. (2016) · Nature Materials · doi:10.1038/nmat4482 · Cited by 132
Engineering multifunctional dynamic hydrogel for biomedical and tissue regenerative applications
Yin, B., Gosecka, M., Bodaghi, M., Crespy, D., Youssef, G., Dodda, J. M., Wong, S. H. D., Imran, A. B., Gosecki, M., Jobdeedamrong, A., et al. (2024) · Chemical Engineering Journal · doi:10.1016/j.cej.2024.150403 · Cited by 150
Khalilgharibi, N., & Mao, Y. (2021) · Open Biology · doi:10.1098/rsob.200360 · Cited by 167
“Changes in ECM composition due to cancer often result in stiffer matrices that can affect cell behaviours through signalling pathways and contribute to malignancy [107,108].”
BackgroundBiomimetic Model of Tumor Microenvironment on Microfluidic Platform
Chung, M., Ahn, J., Son, K., Kim, S., & Jeon, N. L. (2017) · Advanced Healthcare Materials · doi:10.1002/adhm.201700196 · Cited by 126
Tunable Collagen I Hydrogels for Engineered Physiological Tissue Micro-Environments
Antoine, E. E., Vlachos, P. P., & Rylander, M. N. (2015) · PLOS ONE · doi:10.1371/journal.pone.0122500 · Cited by 125
TRPV4 Regulates Breast Cancer Cell Extravasation, Stiffness and Actin Cortex
Lee, W. H., Choong, L. Y., Mon, N. N., Lu, S., Lin, Q., Pang, B., Yan, B., Krishna, V. S. R., Singh, H., Tan, T. Z., et al. (2016) · Scientific Reports · doi:10.1038/srep27903 · Cited by 125
Rigid tumours contain soft cancer cells
Fuhs, T., Wetzel, F., Fritsch, A. W., Li, X., Stange, R., Pawlizak, S., Kießling, T. R., Morawetz, E. W., Grosser, S., Sauer, F. D., et al. (2022) · Nature Physics · doi:10.1038/s41567-022-01755-0 · Cited by 130
The Mammary Gland: Basic Structure and Molecular Signaling during Development
Biswas, S. K., Banerjee, S., Baker, G. W., Kuo, C.-Y., & Chowdhury, I. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms23073883 · Cited by 173
Metastasis in context: modeling the tumor microenvironment with cancer-on-a-chip approaches
Sleeboom, J. J. F., Eslami Amirabadi, H., Nair, P., Sahlgren, C. M., & den Toonder, J. M. J. (2018) · Disease Models & Mechanisms · doi:10.1242/dmm.033100 · Cited by 122
Xin, Y., Li, K., Huang, M. L., Liang, C., Siemann, D. W., Wu, L., Tan, Y., & Tang, X. (2023) · Oncogene · doi:10.1038/s41388-023-02844-x · Cited by 134
“Mouse tumor mammary tissue is 24-fold stiffer than healthy mammary tissue [11].”
BackgroundCell softness regulates tumorigenicity and stemness of cancer cells
Lv, J., Liu, Y., Cheng, F., Li, J., Zhou, Y., Zhang, T., Zhou, N., Li, C., Wang, Z., Ma, L., et al. (2020) · The EMBO Journal · doi:10.15252/embj.2020106123 · Cited by 142
“Published reports have shown a positive association between increased tissue stiffness and aggressive cancer behavior, prompting to propose a model of cancer progression that depends on static or dynamic tumor tissue stiffening (Paszek et al , 2005; Wei et al , 2015; Ondeck et al , 2019).”
Mechanical Regulation of Transcription: Recent Advances
Wagh, K., Ishikawa, M., Garcia, D. A., Stavreva, D. A., Upadhyaya, A., & Hager, G. L. (2021) · Trends in Cell Biology · doi:10.1016/j.tcb.2021.02.008 · Cited by 140
“For example, during the early stages of tumorigenesis, genetic alterations lead to ECM stiffening in the stroma, which facilitates signaling pathways that, through enhanced integrin-mediated mechanotransduction, lead to proliferation and transformation, shifting the balance away from tissue homeostasis (Figure 4B) [62…”
BackgroundEffect of Nuclear Stiffness on Cell Mechanics and Migration of Human Breast Cancer Cells
Fischer, T., Hayn, A., & Mierke, C. T. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00393 · Cited by 145
“The rat and bovine mixture of a 1:2 monomer mass ratio has been shown to provide more physiological elastic properties than pure rat tail collagen matrices (Paszek et al., 2005; Antoine et al., 2014; Lang et al., 2015).”
BackgroundMethodExtracellular Matrix Stiffness: New Areas Affecting Cell Metabolism
Ge, H., Tian, M., Pei, Q., Tan, F., & Pei, H. (2021) · Frontiers in Oncology · doi:10.3389/fonc.2021.631991 · Cited by 139
Epithelial and stromal co-evolution and complicity in pancreatic cancer
Hingorani, S. R. (2023) · Nature Reviews Cancer · doi:10.1038/s41568-022-00530-w · Cited by 108
MRTF potentiates TEAD‐YAP transcriptional activity causing metastasis
Kim, T., Hwang, D., Lee, D., Kim, J., Kim, S., & Lim, D. (2017) · The EMBO Journal · doi:10.15252/embj.201695137 · Cited by 114
LeSavage, B. L., Zhang, D. H., Huerta-López, C., Gilchrist, A. E., Krajina, B. A., Karlsson, K., Smith, A. R., Karagyozova, K., Klett, K. C., Huang, M. S., et al. (2024) · Nature Materials · doi:10.1038/s41563-024-01908-x · Cited by 147
“13 and 14, barcode frequencies at passage 3 within each matrix were normalized by their initial frequency in the parent population.”
Bourgot, I., Primac, I., Louis, T., Noël, A., & Maquoi, E. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01488 · Cited by 113
Stiff stroma increases breast cancer risk by inducing the oncogene ZNF217
Northey, J. J., Barrett, A. S., Acerbi, I., Hayward, M.-K., Talamantes, S., Dean, I. S., Mouw, J. K., Ponik, S. M., Lakins, J. N., Huang, P., et al. (2020) · Journal of Clinical Investigation · doi:10.1172/jci129249 · Cited by 119
“MCF10A cells (ATCC) were cultured as described previously (34) with”
MethodSelf-citationBruce, A., Evans, R., Mezan, R., Shi, L., Moses, B. S., Martin, K. H., Gibson, L. F., & Yang, Y. (2015) · PLOS ONE · doi:10.1371/journal.pone.0140506 · Cited by 112
Collagen Density Modulates the Immunosuppressive Functions of Macrophages
Larsen, A. M. H., Kuczek, D. E., Kalviša, A., Siersbæk, M. S., Thorseth, M., Johansen, A. Z., Carretta, M., Grøntved, L., Vang, O., & Madsen, D. H. (2020) · The Journal of Immunology · doi:10.4049/jimmunol.1900789 · Cited by 125
“(12), and the stimulation of malignant transformation of two breast epithelial cell lines when cultured on stiff matrices (16).”
BackgroundCancer-Associated Fibroblasts: Versatile Players in the Tumor Microenvironment
Ganguly, D., Chandra, R., Karalis, J. D., Teke, M. E., Aguilera, T. A., Maddipati, R., Wachsmann, M., Ghersi, D., Siravegna, G., Zeh, H. J., et al. (2020) · Cancers · doi:10.3390/cancers12092652 · Cited by 130
“For example, by creating a desmoplastic tumor stroma with different degrees of stiffness, CAFs facilitate focal adhesion formation while providing pro-survival signaling to cancer cells [79].”
BackgroundAdhesion-mediated mechanosignaling forces mitohormesis
Tharp, K. M., Higuchi‐Sanabria, R., Timblin, G. A., Ford, B., Garzón-Coral, C., Schneider, C. P., Muncie, J. M., Stashko, C., Daniele, J. R., Moore, A. S., et al. (2021) · Cell Metabolism · doi:10.1016/j.cmet.2021.04.017 · Cited by 147
“V737N b1 integrin, see associated section of STAR Methods for sequence (Paszek et al., 2005) N/A”
InfluentialSelf-citationNaqvi, S. M., & McNamara, L. M. (2020) · Frontiers in Bioengineering and Biotechnology · doi:10.3389/fbioe.2020.597661 · Cited by 131
Yue, X., Nguyen, T. D., Zellmer, V., Zhang, S., & Zorlutuna, P. (2018) · Biomaterials · doi:10.1016/j.biomaterials.2018.04.001 · Cited by 97
Mechanosensing in macrophages and dendritic cells in steady-state and disease
Lee, M., Du, H., Winer, D. A., Clemente-Casares, X., & Tsai, S. (2022) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2022.1044729 · Cited by 99
Demou, Z. N. (2010) · Annals of Biomedical Engineering · doi:10.1007/s10439-010-0097-0 · Cited by 96
Integrin and Its Associated Proteins as a Mediator for Mechano-Signal Transduction
Katoh, K. (2025) · Biomolecules · doi:10.3390/biom15020166 · Cited by 114
Advances in Multifunctional Bioactive Coatings for Metallic Bone Implants
Nikolova, M. P., & Apostolova, M. D. (2022) · Materials · doi:10.3390/ma16010183 · Cited by 117
A Beginner’s Guide to the Characterization of Hydrogel Microarchitecture for Cellular Applications
Martinez-Garcia, F. D., Fischer, T., Hayn, A., Mierke, C. T., Burgess, J. K., & Harmsen, M. C. (2022) · Gels · doi:10.3390/gels8090535 · Cited by 119
“Hydrogels are 2D and 3D cell culture platforms that mimic the ECM and are used in 3D bioprinting and the field of tissue engineering and regenerative medicine (TERM) for cell and drug delivery [8,11,85,154,155].”
BackgroundInfluentialThe Mechanics of Mitotic Cell Rounding
Taubenberger, A., Baum, B., & Matthews, H. K. (2020) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2020.00687 · Cited by 92
Jurj, A. M., Ionescu, C., Berindan‐Neagoe, I., & Braicu, C. (2022) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-022-02484-1 · Cited by 113
“An increased deposition of matrix proteins stimulates tumor progression by interfering with cell polarity, cell-to-cell adhesion as well as growth factor-mediated signalling [92].”
BackgroundTAGLN mediated stiffness-regulated ovarian cancer progression via RhoA/ROCK pathway
Xiao, W., Lou, H., Zhou, D., Jia, Y., Li, H., Huang, Q., Ma, J., Yang, Z., Sun, C., Meng, Y., et al. (2021) · Journal of Experimental & Clinical Cancer Research · doi:10.1186/s13046-021-02091-6 · Cited by 100
“Tumors are often stiffer than normal tissues [5–7], frequently detected through physical palpation as a rigid mass residing within a compliant tissue [5].”
Sun, X.-Y., Cui, B., Yuan, B., Wang, X.-L., Fan, L.-L., Yu, D., He, Z.-Z., Sheng, L., Liu, J., & Lu, J. (2020) · Advanced Functional Materials · doi:10.1002/adfm.202003359 · Cited by 91
Active biomaterials for mechanobiology
Özkale, B., Sakar, M. S., & Mooney, D. J. (2020) · Biomaterials · doi:10.1016/j.biomaterials.2020.120497 · Cited by 106
“These studies revealed that alterations in the physical interactions of cells with the ECM are alone sufficient to drive various biological processes such as migration [9], [10], epithelial-mesenchymal transition [11], [12], and stem cell differentiation [13], [14].”
BackgroundYang, N., Chen, T., Wang, L., Liu, R., Niu, Y., Sun, L., Yao, B., Wang, Y., Yang, W., Liu, Q., et al. (2020) · Theranostics · doi:10.7150/thno.44789 · Cited by 97
“Liver fibrosis was pathologically correlated with increased rigidity of the extracellular matrix (ECM), involving multiple signal transduction pathways that regulate HCC development [8, 9].”
BackgroundXie, N., Xiao, C., Shu, Q., Cheng, B., Wang, Z., Xue, R., Zhang, W., Wang, J., Shi, H., Fan, D., et al. (2022) · Acta Biomaterialia · doi:10.1016/j.actbio.2023.01.039 · Cited by 90
Gill, B. J., & West, J. L. (2014) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2013.09.029 · Cited by 86
3D Cell Culture: Recent Development in Materials with Tunable Stiffness
Baruffaldi, D., Palmara, G., Pirri, C. F., & Frascella, F. (2021) · ACS Applied Bio Materials · doi:10.1021/acsabm.0c01472 · Cited by 106
Li, X., Pan, J., Liu, T., Yin, W., Miao, Q., Zhao, Z., Gao, Y., Zheng, W., Li, H., Deng, R., et al. (2022) · Gut · doi:10.1136/gutjnl-2022-327913 · Cited by 89
Modelling the complex nature of the tumor microenvironment: 3D tumor spheroids as an evolving tool
Rodrigues, D. B., Reis, R. L., & Pirraco, R. P. (2024) · Journal of Biomedical Science · doi:10.1186/s12929-024-00997-9 · Cited by 84
Membrane Ruffling is a Mechanosensor of Extracellular Fluid Viscosity
Pittman, M., Iu, E., Li, K., Wang, M.-J., Chen, J., Taneja, N., Jo, M., Park, S., Jung, W.-H., Liang, L., et al. (2022) · Nature Physics · doi:10.1038/s41567-022-01676-y · Cited by 85
“g, phase diagram generated by the model after inputting experimental measurements shows that given the observations that in a viscous medium, (1) FA assembly/disassembly increases, (2) protrusion increases and (3) FA area decreases, cortical tension is predicted to decrease as the spread area increases on elevated vis…”
MethodBuoso, E., Masi, M., Racchi, M., & Corsini, E. (2020) · International Journal of Molecular Sciences · doi:10.3390/ijms21239229 · Cited by 104
The Role of the ECM in Lung Cancer Dormancy and Outgrowth
Parker, A. L., & Cox, T. R. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.01766 · Cited by 95
Fallica, B., Maffei, J. S., Villa, S., Makin, G., & Zaman, M. (2012) · PLoS ONE · doi:10.1371/journal.pone.0048024 · Cited by 84
The Role of Extracellular Matrix Proteins in Breast Cancer
Lepucki, A., Orlińska, K., Mielczarek‐Palacz, A., Kabut, J., Olczyk, P., & Komosińska‐Vassev, K. (2022) · Journal of Clinical Medicine · doi:10.3390/jcm11051250 · Cited by 104
“A collagen scaffold can be used by cancer cells during migration in order to facilitate this process [140,223,224].”
BackgroundHypoxia Promotes Breast Cancer Cell Growth by Activating a Glycogen Metabolic Program
Tang, K., Zhu, L., Chen, J., Wang, D., Zeng, L., Chen, C., Tang, L. V., Zhou, L., Wei, K., Zhou, Y., et al. (2021) · Cancer Research · doi:10.1158/0008-5472.can-21-0753 · Cited by 108
Cell Shape and Durotaxis Explained from Cell-Extracellular Matrix Forces and Focal Adhesion Dynamics
Rens, E. G., & Merks, R. M. H. (2020) · iScience · doi:10.1016/j.isci.2020.101488 · Cited by 93
Cell spheroid fusion: beyond liquid drops model
Kosheleva, N., Efremov, Y., Shavkuta, B., Zurina, I., Zhang, D.-Y., Zhang, Y.-Y., Minaev, N., Gorkun, A., Wei, S.-C., Shpichka, A., et al. (2020) · Scientific Reports · doi:10.1038/s41598-020-69540-8 · Cited by 84
Deng, M., Lin, J., Nowsheen, S., Liu, T., Zhao, Y., Villalta, P. W., Sicard, D., Tschumperlin, D. J., Lee, S., Kim, J.-J., et al. (2020) · Science Advances · doi:10.1126/sciadv.abb2630 · Cited by 95
“1, A to C) ( 29 – 33 ).”
Cellular modulation by the elasticity of biomaterials
Han, F., Zhu, C., Guo, Q., Yang, H., & Li, B. (2016) · Journal of Materials Chemistry B · doi:10.1039/c5tb02077h · Cited by 83
Elasticity-Dependent Modulation of TGF-β Responses in Human Trabecular Meshwork Cells
Han, H., Wecker, T., Grehn, F., & Schlunck, G. (2011) · Investigative Opthalmology & Visual Science · doi:10.1167/iovs.10-6640 · Cited by 79
Miroshnikova, Y. A., Jorgens, D. M., Spirio, L., Auer, M., Sarang-Sieminski, A. L., & Weaver, V. M. (2011) · Physical Biology · doi:10.1088/1478-3975/8/2/026013 · Cited by 82
Self-citationRojas, A., Añazco, C., González, I., & Araya, P. (2018) · Carcinogenesis · doi:10.1093/carcin/bgy012 · Cited by 82
The role of biomechanical stress in extracellular vesicle formation, composition and activity
Thompson, W., & Papoutsakis, E. T. (2023) · Biotechnology Advances · doi:10.1016/j.biotechadv.2023.108158 · Cited by 94
Song, K., Yu, Z., Zu, X., Li, G., Hu, Z., & Xue, Y. (2022) · International Journal of Molecular Sciences · doi:10.3390/ijms231810509 · Cited by 97
“ECM could not only act as a medium to conduct signals but also elicits biochemical and biophysical signaling to excite cells [1,2].”
BackgroundMondrinos, M. J., Alisafaei, F., Yi, A. Y., Ahmadzadeh, H., Lee, I., Blundell, C., Seo, J., Osborn, M., Jeon, T., Kim, S. M., et al. (2021) · Science Advances · doi:10.1126/sciadv.abe9446 · Cited by 86
Mieulet, V., Garnier, C., Kieffer, Y., Guilbert, T., Nemati, F., Marangoni, E., Renault, G., Chamming’s, F., Vincent-Salomon, A., & Mechta-Grigoriou, F. (2021) · Scientific Reports · doi:10.1038/s41598-021-83685-0 · Cited by 79
Fanfone, D., Wu, Z., Mammi, J., Berthenet, K., Neves, D., Weber, K., Halaburkova, A., Virard, F., Bunel, F., Jamard, C., et al. (2022) · eLife · doi:10.7554/elife.73150 · Cited by 105
Targeting extracellular matrix stiffness for cancer therapy
Feng, X., Cao, F., Wu, X., Xie, W., Wang, P., & Jiang, H. (2024) · Frontiers in Immunology · doi:10.3389/fimmu.2024.1467602 · Cited by 77
Vaish, U., Jain, T., Are, A. C., & Dudeja, V. (2021) · International Journal of Molecular Sciences · doi:10.3390/ijms222413408 · Cited by 102
“It also restricts drug delivery and triggers pro-survival signaling in cancer cells [58].”
BackgroundTumor-Associated Extracellular Matrix: How to Be a Potential Aide to Anti-tumor Immunotherapy?
He, Y., Liu, T., Dai, S., Xu, Z., Wang, L., & Luo, F. (2021) · Frontiers in Cell and Developmental Biology · doi:10.3389/fcell.2021.739161 · Cited by 85
Knops, A. M., South, A., Rodeck, U., Martinez-Outschoorn, U., Harshyne, L., Johnson, J., Luginbuhl, A., & Curry, J. (2020) · Frontiers in Oncology · doi:10.3389/fonc.2020.565306 · Cited by 76
“Through secretion of cytokines like transforming growth factor-beta (TGF-b), CAFs induce a desmoplastic response in the surrounding environment, synthesizing collagen which stiffens the tissue and alters homeostasis (47).”
BackgroundHarnessing nanomedicine to overcome the immunosuppressive tumor microenvironment
Sun, B., Hyun, H., Li, L., & Wang, A. Z. (2020) · Acta Pharmacologica Sinica · doi:10.1038/s41401-020-0424-4 · Cited by 91
“Moreover, the dense and stiff ECM increases IFP and affects the transcapillary transport and diffusion of nanomedicines in the tumor interstitium [120, 121], limiting the distribution of nanocarriers to the vicinity of perivascular regions [122].”
BackgroundFiber density modulates cell spreading in 3D interstitial matrix mimetics
Matera, D. L., Wang, W. Y., Smith, M. R., Shikanov, A., & Baker, B. M. (2019) · ACS Biomaterials Science & Engineering · doi:10.1021/acsbiomaterials.9b00141 · Cited by 75
Revisiting the role of cancer-associated fibroblasts in tumor microenvironment
Lan, X., Li, W., Zhao, K., Wang, J., Li, S., & Hai, Z. (2025) · Frontiers in Immunology · doi:10.3389/fimmu.2025.1582532 · Cited by 75
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
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
