Mechanotransduction of fluid stresses governs 3D cell migration
Open accessAbstract
Significance: Interstitial flow (IF) is elevated in solid tumors and imparts fluid stresses on tumor cells within the extracellular matrix (ECM), and these fluid stresses must be balanced by stress in matrix adhesions to maintain static equilibrium. This force balance results in greater matrix adhesion tension on the upstream side of the cell, and we demonstrate that this tension activates β1-integrin adhesion complexes, resulting in localization and activation of focal adhesion (FA) proteins near the upstream membrane. Importantly, we demonstrate that this asymmetric FA activation governs the direction of cell migration in 3D, and therefore our data show that mechanical stress acting on cells within a 3D ECM is a fundamental directional migratory stimulus.
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
Integrity signals
Registry
Cites
Statistics
Claims the paper makes
The claims and statistics of this paper haven’t been checked yet.
Run the check — free, no account needed. It reads the open-access text and checks the sources it cites.
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?
Most research is focused on how IFP prompts cancer cell migration and metastasis.
“Most research is focused on how IFP prompts cancer cells migration and metastasis [157,[167][168][169].”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [168]
The introduction (p. 2) says elevated interstitial fluid pressure drives interstitial flow that influences tumor-cell migration. The Discussion (p. 6) links this mechanism to metastasis as a possible implication, but does not demonstrate that it causes metastasis or establish that most research focuses on this question. (LLM, conf=0.84)
Experimental — accuracy not yet measuredThe pressure gradient in a microfluidic platform induces cell adhesion activation, cell polarization along flow direction, and migration towards regions with higher pressures.
“The pressure gradient was found out to induce cell adhesion activation, cell polarization along flow direction and migration towards regions with higher pressures.”
From Microfluidic modelling of the tumor microenvironment for anti-cancer drug development (2019) · cites this paper as [168]
Through precise microfluidic designs, microfluidic devices can reconstruct physiological dynamic characteristics in tissues, such as physiological flow, shear stress, nutrient delivery, and drug action, in a controllable environment.
“Through precise microfluidic designs, microfluidic devices can reconstruct physiological dynamic characteristics in tissues, such as physiological flow, shear stress, nutrient delivery, and drug action, in a controllable environment, providing a platform for cell culture, microenvironment creation, and organ simulation or in vitro assessment of organ tissue60–67.”
From Tumor-on-a-chip: from bioinspired design to biomedical application (2021) · cites this paper as [65]
Self-check
Percentages, sums and reported differences re-computed from the paper’s own numbers.
The self-check needs the paper’s full text.
Cites
Cell Movement Is Guided by the Rigidity of the Substrate
Lo, C.-M., Wang, H.-B., Dembo, M., & Wang, Y.-L. (2000) · Biophysical Journal · doi:10.1016/s0006-3495(00)76279-5 · Cited by 3,289 · see citing works
Mechanotransduction Across the Cell Surface and Through the Cytoskeleton
Wang, N., Butler, J. P., & Ingber, D. E. (1993) · Science · doi:10.1126/science.7684161 · Cited by 3,007 · see citing works
Self-citationBalaban, N. Q., Schwarz, U. S., Riveline, D., Goichberg, P., Tzur, G., Sabanay, I., Mahalu, D., Safran, S. A., Bershadsky, A. D., Addadi, L., et al. (2001) · Nature Cell Biology · doi:10.1038/35074532 · Cited by 2,137 · see citing works
Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics
Grashoff, C., Hoffman, B. D., Brenner, M. D., Zhou, R., Parsons, M., Yang, M. T., McLean, M. A., Sligar, S. G., Chen, C. S., Ha, T., et al. (2010) · Nature · doi:10.1038/nature09198 · Cited by 1,549 · see citing works
Stretching Single Talin Rod Molecules Activates Vinculin Binding
Hernández, A. E. D. R., Pérez‐Jiménez, R., Liu, R., Roca‐Cusachs, P., Fernández, J. M., & Sheetz, M. P. (2009) · Science · doi:10.1126/science.1162912 · Cited by 1,509 · see citing works
Focal Contacts as Mechanosensors
Riveline, D., Zamir, E., Balaban, N. Q., Schwarz, U. S., Ishizaki, T., Narumiya, S., Kam, Z., Geiger, B., & Bershadsky, A. D. (2001) · The Journal of Cell Biology · doi:10.1083/jcb.153.6.1175 · Cited by 1,421 · see citing works
Integrin function: molecular hierarchies of cytoskeletal and signaling molecules.
Miyamoto, S., Teramoto, H., Coso, O. A., Gutkind, J. S., Burbelo, P. D., Akiyama, S. K., & Yamada, K. M. (1995) · The Journal of Cell Biology · doi:10.1083/jcb.131.3.791 · Cited by 1,202 · see citing works
Role of extracellular matrix assembly in interstitial transport in solid tumors.
Netti, P. A., Berk, D. A., Swartz, M. A., Grodzinsky, A. J., & Jain, R. K. (2000) · PubMed · Cited by 1,165 · see citing works
The relationship between force and focal complex development
Galbraith, C. G., Yamada, K. M., & Sheetz, M. P. (2002) · The Journal of Cell Biology · doi:10.1083/jcb.200204153 · Cited by 908 · see citing works
Plotnikov, S. V., Pasapera, A. M., Sabass, B., & Waterman, C. M. (2012) · Cell · doi:10.1016/j.cell.2012.11.034 · Cited by 866 · see citing works
Choi, C. K., Vicente-Manzanares, M., Zareno, J., Whitmore, L. A., Mogilner, A., & Horwitz, A. R. (2008) · Nature Cell Biology · doi:10.1038/ncb1763 · Cited by 797 · see citing works
Microfluidic assay for simultaneous culture of multiple cell types on surfaces or within hydrogels
Shin, Y., Han, S., Jeon, J. S., Yamamoto, K., Zervantonakis, I. K., Sudo, R., Kamm, R. D., & Chung, S. (2012) · Nature Protocols · doi:10.1038/nprot.2012.051 · Cited by 617 · see citing works
Self-citationDelivery of Molecular and Nanoscale Medicine to Tumors: Transport Barriers and Strategies
Chauhan, V. P., Stylianopoulos, T., Boucher, Y., & Jain, R. K. (2011) · Annual Review of Chemical and Biomolecular Engineering · doi:10.1146/annurev-chembioeng-061010-114300 · Cited by 597 · see citing works
Pasapera, A. M., Schneider, I. C., Rericha, E. C., Schlaepfer, D. D., & Waterman, C. M. (2010) · The Journal of Cell Biology · doi:10.1083/jcb.200906012 · Cited by 573 · see citing works
Shields, J. D., Fleury, M. E., Yong, C., Tomei, A. A., Randolph, G. J., & Swartz, M. A. (2007) · Cancer Cell · doi:10.1016/j.ccr.2007.04.020 · Cited by 555 · see citing works
Boucher, Y., & Jain, R. K. (1992) · PubMed · Cited by 510 · see citing works
Interstitial flow influences direction of tumor cell migration through competing mechanisms
Polacheck, W. J., Charest, J. L., & Kamm, R. D. (2011) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.1103581108 · Cited by 509 · see citing works
Self-citationFocal adhesion kinase is involved in mechanosensing during fibroblast migration
Wang, H.-B., Dembo, M., Hanks, S. K., & Wang, Y. (2001) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.201201198 · Cited by 503 · see citing works
Stylianopoulos, T., Martin, J. D., Snuderl, M., Mpekris, F., Jain, S. R., & Jain, R. K. (2013) · Cancer Research · doi:10.1158/0008-5472.can-12-4521 · Cited by 481 · see citing works
A paxillin tyrosine phosphorylation switch regulates the assembly and form of cell-matrix adhesions
Zaidel‐Bar, R., Milo, R., Kam, Z., & Geiger, B. (2006) · Journal of Cell Science · doi:10.1242/jcs.03314 · Cited by 475 · see citing works
Parker, K. K., Brock, A., Brangwynne, C., Mannix, R. J., Wang, N., Ostuni, E., Geisse, N. A., Adams, J. C., Whitesides, G. M., & Ingber, D. E. (2002) · The FASEB Journal · doi:10.1096/fj.02-0038com · Cited by 460 · see citing works
Self-citationMolecular diversity of cell-matrix adhesions
Zamir, E., Katz, B.-Z., Aota, S., Yamada, K. M., Geiger, B., & Kam, Z. (1999) · Journal of Cell Science · doi:10.1242/jcs.112.11.1655 · Cited by 459 · see citing works
Fluid Shear Stress Activation of Focal Adhesion Kinase
Li, S., Kim, M. S., Hu, Y., Jalali, S., Schlaepfer, D. D., Hunter, T. R., Chien, S., & Shyy, J. Y.-J. (1997) · Journal of Biological Chemistry · doi:10.1074/jbc.272.48.30455 · Cited by 414 · see citing works
Moore, S. W., Roca‐Cusachs, P., & Sheetz, M. P. (2010) · Developmental Cell · doi:10.1016/j.devcel.2010.07.018 · Cited by 407 · see citing works
Cell-Cell Mechanical Communication through Compliant Substrates
Reinhart‐King, C. A., Dembo, M., & Hammer, D. A. (2008) · Biophysical Journal · doi:10.1529/biophysj.107.127662 · Cited by 391 · see citing works
Nonpolarized signaling reveals two distinct modes of 3D cell migration
Petrie, R. J., Gavara, N., Chadwick, R. S., & Yamada, K. M. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201201124 · Cited by 375 · see citing works
A driving force for change: interstitial flow as a morphoregulator
Rutkowski, J. M., & Swartz, M. A. (2006) · Trends in Cell Biology · doi:10.1016/j.tcb.2006.11.007 · Cited by 303 · see citing works
Chan, K. T., Cortesio, C. L., & Huttenlocher, A. (2009) · The Journal of Cell Biology · doi:10.1083/jcb.200809110 · Cited by 258 · see citing works
(2001) · PubMed · Cited by 257 · see citing works
Tumor cell migration in complex microenvironments
Polacheck, W. J., Zervantonakis, I. K., & Kamm, R. D. (2012) · Cellular and Molecular Life Sciences · doi:10.1007/s00018-012-1115-1 · Cited by 222 · see citing works
Self-citationYeon, J. H., Ryu, H. R., Chung, M., Hu, Q. P., & Jeon, N. L. (2012) · Lab on a Chip · doi:10.1039/c2lc40131b · Cited by 179 · see citing works
Migration dynamics of breast cancer cells in a tunable 3D interstitial flow chamber
Haessler, U., Teo, J. C. M., Foretay, D., Renaud, P., & Swartz, M. A. (2012) · Integrative Biology · doi:10.1039/c1ib00128k · Cited by 176 · see citing works
Cellular Fluid Mechanics and Mechanotransduction
Tarbell, J. M., Weinbaum, S., & Kamm, R. D. (2005) · Annals of Biomedical Engineering · doi:10.1007/s10439-005-8775-z · Cited by 155 · see citing works
Self-citationAhmed, N., Riley, C. B., Rice, G. E., & Quinn, M. A. (2005) · Clinical & Experimental Metastasis · doi:10.1007/s10585-005-1262-y · Cited by 140 · see citing works
Vickerman, V., & Kamm, R. D. (2012) · Integrative Biology · doi:10.1039/c2ib00184e · Cited by 126 · see citing works
Self-citationGrisaru‐Granovsky, S., Salah, Z., Maoz, M., et al. (2004) · International Journal of Cancer · doi:10.1002/ijc.20607 · Cited by 116 · see citing works
Ensemble Analysis of Angiogenic Growth in Three-Dimensional Microfluidic Cell Cultures
Farahat, W. A., Wood, L. B., Zervantonakis, I. K., Schor, A. R., Ong, L. S., Neal, D. M., Kamm, R. D., & Asada, H. H. (2012) · PLoS ONE · doi:10.1371/journal.pone.0037333 · Cited by 114 · see citing works
Self-citationHofmann, M., Guschel, M., Bernd, A., Bereiter-Hahn, J., Kaufmann, R., Tandi, C., Wiig, H., & Kippenberger, S. (2006) · Neoplasia · doi:10.1593/neo.05469 · Cited by 106 · see citing works
Formation of Human Capillaries In Vitro : The Engineering of Prevascularized Matrices
Montaño, I., Schiestl, C. M., Schneider, J., Pontiggia, L., Luginbühl, J., Biedermann, T., Sophie Böttcher-haberzeth, A., Braziulis, E., Meuli, M., & Ernst Reichmann, A. (2009) · Tissue Engineering Part A · doi:10.1089/ten.tea.2008.0550 · Cited by 105 · see citing works
Pedersen, J. A., Lichter, S., & Swartz, M. A. (2009) · Journal of Biomechanics · doi:10.1016/j.jbiomech.2009.11.007 · Cited by 97 · see citing works
Cell Stiffening in Response to External Stress is Correlated to Actin Recruitment
Arcizet, D., Cardoso, O., Richert, A., & Hénon, S. (2008) · Biophysical Journal · doi:10.1529/biophysj.107.118265 · Cited by 97 · see citing works
2D protrusion but not motility predicts growth factor–induced cancer cell migration in 3D collagen
Meyer, A. S., Hughes, S. K., Kay, J. E., Castillo, A., Wells, A. H., Gertler, F. B., & Lauffenburger, D. A. (2012) · The Journal of Cell Biology · doi:10.1083/jcb.201201003 · Cited by 94 · see citing works
Shi, Z., Wang, H., & Tarbell, J. M. (2011) · PLoS ONE · doi:10.1371/journal.pone.0015956 · Cited by 88 · see citing works
Diverse Roles for the Paxillin Family of Proteins in Cancer
Deakin, N. O., Pignatelli, J., & Turner, C. E. (2012) · Genes & Cancer · doi:10.1177/1947601912458582 · Cited by 81 · see citing works
Allioux-Guérin, M., Arcizet, D., Durieux, C., Hénon, S., Gallet, F., Mevel, J., Masse, M.-J., Tramier, M., & Coppey‐Moisan, M. (2008) · Biophysical Journal · doi:10.1529/biophysj.108.134627 · Cited by 56 · see citing works
Sero, J., Thodeti, C. K., Mammoto, A., Bakal, C., Thomas, S. Μ., & Ingber, D. E. (2011) · PLoS ONE · doi:10.1371/journal.pone.0028303 · Cited by 54 · see citing works
Self-citationCreeping Flow past a Solid Sphere in a Porous Medium
Ganapathy, R. (1997) · ZAMM ‐ Journal of Applied Mathematics and Mechanics / Zeitschrift für Angewandte Mathematik und Mechanik · doi:10.1002/zamm.19970771113 · Cited by 28 · see citing works
Paxillin controls directional cell motility in response to physical cues
Sero, J., German, A. E., Mammoto, A., et al. (2012) · Cell Adhesion & Migration · doi:10.4161/cam.21672 · Cited by 24 · see citing works
Self-citation
Flagged first, then by citations
Cited by
Sorted by citations
Advances in organ-on-a-chip engineering
Zhang, B., Korolj, A., Lai, B. F. L., & Radisic, M. (2018) · Nature Reviews Materials · doi:10.1038/s41578-018-0034-7 · Cited by 1,017 · see citing works
Organoid-on-a-chip and body-on-a-chip systems for drug screening and disease modeling
Skardal, A., Shupe, T., & Atala, A. (2016) · Drug Discovery Today · doi:10.1016/j.drudis.2016.07.003 · Cited by 512 · see citing works
Microfluidic 3D cell culture: from tools to tissue models
van Duinen, V., Trietsch, S. J., Joore, J., Vulto, P., & Hankemeier, T. (2015) · Current Opinion in Biotechnology · doi:10.1016/j.copbio.2015.05.002 · Cited by 500 · see citing works
Tumor-on-a-chip: from bioinspired design to biomedical application
Liu, X., Fang, J., Huang, S., Wu, X., Xie, X., Wang, J., Liu, F., Zhang, M., Peng, Z., & Hu, N. (2021) · Microsystems & Nanoengineering · doi:10.1038/s41378-021-00277-8 · Cited by 246 · see citing works
Biophysics of tumor microenvironment and cancer metastasis – a mini review
Emon, B., Bauer, J., Jain, Y., Jung, B., & Saif, T. (2018) · Computational and Structural Biotechnology Journal · doi:10.1016/j.csbj.2018.07.003 · Cited by 245 · see citing works
Microfluidic modelling of the tumor microenvironment for anti-cancer drug development
Shang, M., Soon, R. H., Lim, C. T., Khoo, B. L., & Han, J. (2019) · Lab on a Chip · doi:10.1039/c8lc00970h · Cited by 227 · see citing works
A review of microfluidic approaches for investigating cancer extravasation during metastasis
Ma, Y.-H. V., Middleton, K., You, L., & Sun, Y. (2018) · Microsystems & Nanoengineering · doi:10.1038/micronano.2017.104 · Cited by 154 · see citing works
Three-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 · see citing works
Flow-induced stress on adherent cells in microfluidic devices
Shemesh, J., Jalilian, I., Shi, A., Heng Yeoh, G., Knothe Tate, M. L., & Ebrahimi Warkiani, M. (2015) · Lab on a Chip · doi:10.1039/c5lc00633c · Cited by 144 · see citing works
Applications of tumor chip technology
Hachey, S. J., & Hughes, C. C. W. (2018) · Lab on a Chip · doi:10.1039/c8lc00330k · Cited by 128 · see citing works
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 · see citing works
Low levels of physiological interstitial flow eliminate morphogen gradients and guide angiogenesis
Shirure, V. S., Lezia, A., Tao, A., Alonzo, L. F., & George, S. C. (2017) · Angiogenesis · doi:10.1007/s10456-017-9559-4 · Cited by 117 · see citing works
Piotrowski-Daspit, A. S., Tien, J., & Nelson, C. M. (2016) · Integrative Biology · doi:10.1039/c5ib00282f · Cited by 101 · see citing works
Huang, Y. L., Tung, C.-K., Zheng, A., Kim, B. J., & Wu, M. (2015) · Integrative Biology · doi:10.1039/c5ib00115c · Cited by 75 · see citing works
Dynamic Microenvironment Induces Phenotypic Plasticity of Esophageal Cancer Cells Under Flow
Calibasi Kocal, G., Güven, S., Foygel, K., Goldman, A., Chen, P., Sengupta, S., Paulmurugan, R., Baskin, Y., & Demirci, U. (2016) · Scientific Reports · doi:10.1038/srep38221 · Cited by 52 · see citing works
- Authors
- Polacheck, W. J., German, A. E., Mammoto, A., Ingber, D. E., & Kamm, R. D.
- Affiliations
- Massachusetts Institute of Technology (US)
- Boston Children's Hospital (US)
- Venue
- Proceedings of the National Academy of Sciences
- Publisher
- National Academy of Sciences
- Published
- 2014-02-03
- Volume
- 111
- Issue
- 7
- Pages
- 2447-2452
- ISSN
- 0027-8424 (ISSN-L)
- 1091-6490
- PMC
- PMC3932905
- OpenAlex
- W2023608795
- Semantic Scholar
- 79bf38f55f93ed240ea8b04349bd1bacd6de7d8e
- Cited by
- 265
- References
- 48
- Citations by year
- 2026: 14 · 2025: 18 · 2024: 22 · 2023: 14 · 2022: 22 · 2021: 28 · 2020: 23 · 2019: 24 · 2018: 32 · 2017: 14 · 2016: 23 · 2015: 21 · 2014: 10
- FWCI
- 11.29
- Type
- journal article
- Language
- en
- Open access
- bronze
- doi.org
- Locations
- Proceedings of the National Academy of Sciences (publishedVersion)
- Europe PMC (PubMed Central) (publishedVersion)
- PubMed Central (publishedVersion)
- PubMed (publishedVersion)
- Digital Access to Scholarship at Harvard (DASH) (Harvard University) (submittedVersion, cc-by)
- DSpace@MIT (Massachusetts Institute of Technology) (submittedVersion, cc-by-nc)
- Funders
- National Cancer Institute (R33CA174550, R21CA140096)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Cellular Mechanics and Interactions
- Health Sciences › Medicine › Immunology and Allergy › Cell Adhesion Molecules Research
- Physical Sciences › Engineering › Biomedical Engineering › 3D Printing in Biomedical Research
- Keywords
- rheotaxis, interstitial fluid flow, mechanotransduction, cell migration, solid tumors, interstitial fluid pressure, β1 integrin activation, focal adhesion kinase, vinculin, actin cytoskeleton, cell polarization, type I collagen gel, fluid drag, microfluidic platform
- MeSH terms
- Cell Movement, Extracellular Matrix, Humans, Models, Biological, Transfection, Vinculin, Integrin beta1, Focal Adhesions, RNA, Small Interfering, Mechanotransduction, Cellular, Extracellular Fluid, Cell Line, Tumor, Green Fluorescent Proteins, Hydrodynamics
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
