Skip to main content

Thank you for visiting nature.com. You are using a browser version with limited support for CSS. To obtain the best experience, we recommend you use a more up to date browser (or turn off compatibility mode in Internet Explorer). In the meantime, to ensure continued support, we are displaying the site without styles and JavaScript.

Balancing forces: architectural control of mechanotransduction

Key Points

  • Cells have complex machinery capable of sensing and responding to mechanical cues from their microenvironment through a process termed mechanotransduction. These cues are typically sensed through force-induced conformational or organizational changes to molecules or structures such as ion channels, cadherin complexes, G protein-coupled receptors, Tyr kinase receptors and integrins, which, upon activation, ultimately trigger downstream signalling pathways that modify cell fate.

  • The interwoven mechanical interactions between neighbouring cells and between cells and their extracellular matrix, as well as through adhesion and filament networks, determine local forces and sites of mechanotransduction. Cumulatively, these nanoscale-level to tissue-level interactions define a cell's mechanical context and provide a high level of control over cellular mechanotransduction and resulting cell behaviour.

  • Mechanical cues have an integral role in directing development, as cell shape and motility are essential for many of the fundamental processes that are involved in embryogenesis. A crucial structural component that directs the mechanical phenotype of tissues during development is the extracellular matrix: its physical state and rigidity direct developmental processes such as cell sorting, differentiation and compartmentalization.

  • Mechanotransduction occurs on a relatively fast timescale, on the order of microseconds to minutes. By contrast, many pathological states, such as cardiovascular disease and cancer, derive from sustained perturbations to mechanotransduction over longer periods of time, lasting months or even years. The extracellular matrix, by virtue of its ability to be dynamically remodelled, is a prime candidate for maintaining these perturbations.

  • The extracellular matrix is a highly stable system that can be equated to a type of memory-storage device that can be 'read' or 'written-to' by cells. In this analogy, information is written to the extracellular matrix by crosslinking enzymes, including lysyl oxidase, and matrix metalloproteinases. Corruption of information through unregulated modifications to the extracellular matrix can be misread by cells, leading to tumour growth, inflammation and metastasis.

Abstract

All cells exist within the context of a three-dimensional microenvironment in which they are exposed to mechanical and physical cues. These cues can be disrupted through perturbations to mechanotransduction, from the nanoscale-level to the tissue-level, which compromises tensional homeostasis to promote pathologies such as cardiovascular disease and cancer. The mechanisms of such perturbations suggest that a complex interplay exists between the extracellular microenvironment and cellular function. Furthermore, sustained disruptions in tensional homeostasis can be caused by alterations in the extracellular matrix, allowing it to serve as a mechanically based memory-storage device that can perpetuate a disease or restore normal tissue behaviour.

This is a preview of subscription content

Access options

Buy article

Get time limited or full article access on ReadCube.

$32.00

All prices are NET prices.

Figure 1: The mechanical network.
Figure 2: Spatio-mechanical regulation of signalling pathways.
Figure 3: The extracellular matrix and tensional homeostasis in development.
Figure 4: Sustaining mechanotransduction.
Figure 5: Tensional homeostasis in tumour progression.

References

  1. Sniadecki, N. J. A tiny touch: activation of cell signaling pathways with magnetic nanoparticles. Endocrinol. 151, 451–457 (2010).

    CAS  Google Scholar 

  2. Monshausen, G. B. & Gilroy, S. Feeling green: mechanosensing in plants. Trends. Cell Biol. 19, 228–235 (2009).

    PubMed  Google Scholar 

  3. van der Flier, A. & Sonnenberg, A. Function and interactions of integrins. Cell Tissue Res. 305, 285–298 (2001).

    CAS  PubMed  Google Scholar 

  4. Zaidel-Bar, R. Evolution of complexity in the integrin adhesome. J. Cell Biol. 186, 317–321 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  5. Jaalouk, D. E. & Lammerding, J. Mechanotransduction gone awry. Nature Rev. Mol. Cell Biol. 10, 63–73 (2009).

    CAS  Google Scholar 

  6. Hamill, O. P. & Martinac, B. Molecular basis of mechanotransduction in living cells. Physiol. Rev. 81, 685–740 (2001).

    CAS  PubMed  Google Scholar 

  7. Ingber, D. E. Cellular mechanotransduction: putting all the pieces together again. FASEB J. 20, 811–827 (2006).

    CAS  PubMed  Google Scholar 

  8. Katsumi, A., Orr, A. W., Tzima, E. & Schwartz, M. A. Integrins in mechanotransduction. J. Biol. Chem. 279, 12001–12004 (2004).

    CAS  PubMed  Google Scholar 

  9. Vogel, V. & Sheetz, M. Local force and geometry sensing regulate cell functions. Nature Rev. Mol. Cell Biol. 7, 265–275 (2006).

    CAS  Google Scholar 

  10. Lansman, J. B., Hallam, T. J. & Rink, T. J. Single stretch-activated ion channels in vascular endothelial cells as mechanotransducers? Nature 325, 811–813 (1987).

    CAS  PubMed  Google Scholar 

  11. Tzima, E. et al. A mechanosensory complex that mediates the endothelial cell response to fluid shear stress. Nature 437, 426–431 (2005).

    CAS  PubMed  Google Scholar 

  12. Felsenfeld, D. P., Schwartzberg, P. L., Venegas, A., Tse, R. & Sheetz, M. P. Selective regulation of integrin-cytoskeleton interactions by the tyrosine kinase Src. Nature Cell Biol. 1, 200–206 (1999).

    CAS  PubMed  Google Scholar 

  13. Giannone, G. & Sheetz, M. P. Substrate rigidity and force define form through tyrosine phosphatase and kinase pathways. Trends Cell Biol. 16, 213–223 (2006).

    CAS  PubMed  Google Scholar 

  14. Chen, K. D. et al. Mechanotransduction in response to shear stress - roles of receptor tyrosine kinases, integrins, and Shc. J. Biol. Chem. 274, 18393–18400 (1999).

    CAS  PubMed  Google Scholar 

  15. Chen, C. S. Mechanotransduction — a field pulling together? J. Cell Sci. 121, 3285–3292 (2008).

    CAS  PubMed  Google Scholar 

  16. Vogel, V. & Sheetz, M. P. Cell fate regulation by coupling mechanical cycles to biochemical signaling pathways. Curr. Opin. Cell Biol. 21, 38–46 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  17. Geiger, B., Spatz, J. P. & Bershadsky, A. D. Environmental sensing through focal adhesions. Nature Rev. Mol. Cell Biol. 10, 21–33 (2009).

    CAS  Google Scholar 

  18. Galbraith, C. G., Yamada, K. M. & Sheetz, M. P. The relationship between force and focal complex development. J. Cell Biol. 159, 695–705 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Friedland, J. C., Lee, M. H. & Boettiger, D. Mechanically activated integrin switch controls α5β1 function. Science 323, 642–644 (2009).

    CAS  PubMed  Google Scholar 

  20. del Rio, A. et al. Stretching single talin rod molecules activates vinculin binding. Science 323, 638–641 (2009). Presents a general role of force transduction, in which the mechanical stretching of single proteins can expose cryptic binding sites for other molecules.

    CAS  PubMed  Google Scholar 

  21. Sawada, Y. et al. Force sensing by mechanical extension of the Src family kinase substrate p130Cas. Cell 127, 1015–1026 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  22. Lee, S. E., Kamm, R. D. & Mofrad, M. R. K. Force-induced activation of Talin and its possible role in focal adhesion mechanotransduction. J. Biomech. 40, 2096–2106 (2007).

    PubMed  Google Scholar 

  23. Bershadsky, A., Kozlov, M. & Geiger, B. Adhesion-mediated mechanosensitivity: a time to experiment, and a time to theorize. Curr. Opin. Cell Biol. 18, 472–481 (2006).

    CAS  PubMed  Google Scholar 

  24. Paszek, M. J., Boettiger, D., Weaver, V. M. & Hammer, D. A. Integrin clustering is driven by mechanical resistance from the Glycocalyx and the substrate. PLoS Comput. Biol. 5, e1000604 (2009).

    PubMed  PubMed Central  Google Scholar 

  25. Miteva, D. O. et al. Transmural flow modulates cell and fluid transport functions of lymphatic endothelium. Circ. Res. 106, 920–931 (2010).

    CAS  PubMed  Google Scholar 

  26. Shields, J. D. et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11, 526–538 (2007). Demonstrates a mechanism for metastasis through which tumour cells are guided to the lymphatic vessels serving the tumour in a force-based process that is facilitated by interstitial flow.

    CAS  PubMed  Google Scholar 

  27. Kopan, R. & Ilagan, M. X. The canonical Notch signaling pathway: unfolding the activation mechanism. Cell 137, 216–233 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  28. Gordon, W. R. et al. Structural basis for autoinhibition of Notch. Nature Struc. Mol. Biol. 14, 295–300 (2007).

    CAS  Google Scholar 

  29. Salaita, K. et al. Restriction of receptor movement alters cellular response: physical force sensing by EphA2. Science 327, 1380–1385 (2010). Physical barriers, termed spatial mutations, were used to demonstrate a broadly applicable process through which EPHA2 signalling pathways could be regulated in a spatio-mechanical mechanism, underscoring the potential of the ECM and cell surface to modulate a broad range of mechanotransduction pathways.

    CAS  PubMed  PubMed Central  Google Scholar 

  30. Costa, M. N., Radhakrishnan, K., Wilson, B. S., Vlachos, D. G. & Edwards, J. S. Coupled stochastic spatial and non-spatial simulations of ErbB1 signaling pathways demonstrate the importance of spatial organization in signal transduction. PLoS ONE 4, e6316 (2009).

    PubMed  PubMed Central  Google Scholar 

  31. Chung, I. et al. Spatial control of EGF receptor activation by reversible dimerization on living cells. Nature 464, 783–787 (2010).

    CAS  PubMed  Google Scholar 

  32. Sako, Y. & Kusumi, A. Barriers for lateral diffusion of transferrin receptor in the plasma membrane as characterized by receptor dragging by laser tweezers: fence versus tether. J. Cell Biol. 129, 1559–1574 (1995).

    CAS  PubMed  Google Scholar 

  33. Kusumi, A. et al. Paradigm shift of the plasma membrane concept from the two-dimensional continuum fluid to the partitioned fluid: high-speed single-molecule tracking of membrane molecules. Annu. Rev. Biophys. Biomol. Struct. 34, 351–378 (2005).

    CAS  PubMed  Google Scholar 

  34. Chrzanowska-Wodnicka, M. & Burridge, K. Rho-stimulated contractility drives the formation of stress fibers and focal adhesions. J. Cell Biol. 133, 1403–1415 (1996).

    CAS  PubMed  Google Scholar 

  35. Girard, P. R. & Nerem, R. M. Shear stress modulates endothelial cell morphology and F-actin organization through the regulation of focal adhesion-associated proteins. J. Cell. Physiol. 163, 179–193 (1995).

    CAS  PubMed  Google Scholar 

  36. Kaunas, R., Nguyen, P., Usami, S. & Chien, S. Cooperative effects of Rho and mechanical stretch on stress fiber organization. Proc. Natl Acad. Sci. USA 102, 15895–15900 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Totsukawa, G. et al. Distinct roles of ROCK (Rho-kinase) and MLCK in spatial regulation of MLC phosphorylation for assembly of stress fibers and focal adhesions in 3T3 fibroblasts. J. Cell Biol. 150, 797–806 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Gaus, K., Le Lay, S., Balasubramanian, N. & Schwartz, M. A. Integrin-mediated adhesion regulates membrane order. J. Cell Biol. 174, 725–734 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Weaver, V. M. et al. β4 integrin-dependent formation of polarized three-dimensional architecture confers resistance to apoptosis in normal and malignant mammary epithelium. Cancer Cell 2, 205–216 (2002).

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Nelson, C. M., Vanduijn, M. M., Inman, J. L., Fletcher, D. A. & Bissell, M. J. Tissue geometry determines sites of mammary branching morphogenesis in organotypic cultures. Science 314, 298–300 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Sikavitsas, V. I., Bancroft, G. N., Holtorf, H. L., Jansen, J. A. & Mikos, A. G. Mineralized matrix deposition by marrow stromal osteoblasts in 3D perfusion culture increases with increasing fluid shear forces. Proc. Natl Acad Sci. USA 100, 14683–14688 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  42. Gomez, E. W., Chen, Q. K., Gjorevski, N. & Nelson, C. M. Tissue geometry patterns epithelial-mesenchymal transition via intercellular mechanotransduction. J. Cell. Biochem. 110, 44–51 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  43. Peerani, R. et al. Niche-mediated control of human embryonic stem cell self-renewal and differentiation. EMBO J. 26, 4744–4755 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  44. Paluch, E. & Heisenberg, C. P. Biology and physics of cell shape changes in development. Curr. Biol. 19, R790–R799 (2009).

    CAS  PubMed  Google Scholar 

  45. Martin, A. C., Kaschube, M. & Wieschaus, E. F. Pulsed contractions of an actin-myosin network drive apical constriction. Nature 457, 495–499 (2009).

    CAS  PubMed  Google Scholar 

  46. Legant, W. R. et al. Microfabricated tissue gauges to measure and manipulate forces from 3D microtissues. Proc. Natl Acad. Sci. USA 106, 10097–10102 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Nelson, C. M. et al. Emergent patterns of growth controlled by multicellular form and mechanics. Proc. Natl Acad. Sci. USA 102, 11594–11599 (2005).

    CAS  PubMed  PubMed Central  Google Scholar 

  48. Ruiz, S. A. & Chen, C. S. Emergence of patterned stem cell differentiation within multicellular structures. Stem Cells 26, 2921–2927 (2008).

    PubMed  PubMed Central  Google Scholar 

  49. Martin, A. C., Gelbart, M., Fernandez-Gonzalez, R., Kaschube, M. & Wieschaus, E. F. Integration of contractile forces during tissue invagination. J. Cell Biol. 188, 735–749 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. Kumar, S. et al. Viscoelastic retraction of single living stress fibers and its impact on cell shape, cytoskeletal organization, and extracellular matrix mechanics. Biophys. J. 90, 3762–3773 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  51. Lele, T. P. et al. Mechanical forces alter zyxin unbinding kinetics within focal adhesions of living cells. J. Cell. Physiol. 207, 187–194 (2006).

    CAS  PubMed  Google Scholar 

  52. Maddugoda, M. P., Crampton, M. S., Shewan, A. M. & Yap, A. S. Myosin VI and vinculin cooperate during the morphogenesis of cadherin cell cell contacts in mammalian epithelial cells. J. Cell Biol. 178, 529–540 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Montell, D. J. Morphogenetic cell movements: diversity from modular mechanical properties. Science 322, 1502–1505 (2008).

    CAS  PubMed  Google Scholar 

  54. Desprat, N., Supatto, W., Pouille, P. A., Beaurepaire, E. & Farge, E. Tissue deformation modulates Twist expression to determine anterior midgut differentiation in Drosophila embryos. Dev. Cell 15, 470–477 (2008). A dramatic demonstration of how mechanical deformations play a crucial and integral role in embryonic morphogenetic movements and have implications across virtually all stages of development.

    CAS  PubMed  Google Scholar 

  55. Pouille, P. A., Ahmadi, P., Brunet, A. C. & Farge, E. Mechanical signals trigger Myosin II redistribution and mesoderm invagination in Drosophila embryos. Sci. Signal. 2, ra16 (2009).

    PubMed  Google Scholar 

  56. Kolsch, V., Seher, T., Fernandez-Ballester, G. J., Serrano, L. & Leptin, M. Control of Drosophila gastrulation by apical localization of adherens junctions and RhoGEF2. Science 315, 384–386 (2007).

    PubMed  Google Scholar 

  57. Fernandez-Gonzalez, R., Simoes Sde, M., Roper, J. C., Eaton, S. & Zallen, J. A. Myosin II dynamics are regulated by tension in intercalating cells. Dev. Cell 17, 736–743 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Solon, J., Kaya-Copur, A., Colombelli, J. & Brunner, D. Pulsed forces timed by a ratchet-like mechanism drive directed tissue movement during dorsal closure. Cell 137, 1331–1342 (2009).

    PubMed  Google Scholar 

  59. Rozario, T., Dzamba, B., Weber, G. F., Davidson, L. A. & DeSimone, D. W. The physical state of fibronectin matrix differentially regulates morphogenetic movements in vivo. Dev. Biol. 327, 386–398 (2009).

    CAS  PubMed  Google Scholar 

  60. Rozario, T. & DeSimone, D. W. The extracellular matrix in development and morphogenesis: a dynamic view. Dev. Biol. 341, 126–140 (2010).

    CAS  PubMed  Google Scholar 

  61. Dzamba, B. J., Jakab, K. R., Marsden, M., Schwartz, M. A. & DeSimone, D. W. Cadherin adhesion, tissue tension, and noncanonical Wnt signaling regulate fibronectin matrix organization. Dev. Cell 16, 421–432 (2009). Provides support for a matrix-assembly model in tissues, in which fibronectin fibril formation at cell surfaces is facilitated by cell–cell adhesions directing tension to the integrins that are required for assembly of the fibronectin matrix.

    CAS  PubMed  PubMed Central  Google Scholar 

  62. Mao, Y. & Schwarzbauer, J. E. Fibronectin fibrillogenesis, a cell-mediated matrix assembly process. Matrix Biol. 24, 389–399 (2005).

    CAS  PubMed  Google Scholar 

  63. Zhong, C. et al. Rho-mediated contractility exposes a cryptic site in fibronectin and induces fibronectin matrix assembly. J. Cell Biol. 141, 539–551 (1998).

    CAS  PubMed  PubMed Central  Google Scholar 

  64. Paszek, M. J. et al. Tensional homeostasis and the malignant phenotype. Cancer Cell 8, 241–254 (2005).

    CAS  PubMed  Google Scholar 

  65. Julich, D., Mould, A. P., Koper, E. & Holley, S. A. Control of extracellular matrix assembly along tissue boundaries via Integrin and Eph/Ephrin signaling. Development 136, 2913–2921 (2009).

    CAS  PubMed  Google Scholar 

  66. Engler, A. J., Sen, S., Sweeney, H. L. & Discher, D. E. Matrix elasticity directs stem cell lineage specification. Cell 126, 677–689 (2006).

    CAS  PubMed  Google Scholar 

  67. Chowdhury, F. et al. Material properties of the cell dictate stress-induced spreading and differentiation in embryonic stem cells. Nature Mater. 9, 82–88 (2010).

    CAS  Google Scholar 

  68. Krieg, M. et al. Tensile forces govern germ-layer organization in zebrafish. Nature Cell Biol. 10, 429–436 (2008).

    CAS  PubMed  Google Scholar 

  69. Foty, R. A. & Steinberg, M. S. The differential adhesion hypothesis: a direct evaluation. Dev. Biol. 278, 255–263 (2005).

    CAS  PubMed  Google Scholar 

  70. Poh, Y. C. et al. Rapid activation of Rac GTPase in living cells by force is independent of Src. PLoS ONE 4, e7886 (2009).

    PubMed  PubMed Central  Google Scholar 

  71. Na, S. et al. Rapid signal transduction in living cells is a unique feature of mechanotransduction. Proc. Natl Acad. Sci. USA 105, 6626–6631 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Wang, Y. et al. Visualizing the mechanical activation of Src. Nature 434, 1040–1045 (2005).

    CAS  PubMed  Google Scholar 

  73. Wang, N., Tytell, J. D. & Ingber, D. E. Mechanotransduction at a distance: mechanically coupling the extracellular matrix with the nucleus. Nature Rev. Mol. Cell Biol. 10, 75–82 (2009).

    CAS  Google Scholar 

  74. Lo, C. M., Wang, H. B., Dembo, M. & Wang, Y. L. Cell movement is guided by the rigidity of the substrate. Biophys. J. 79, 144–152 (2000).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Levental, K. R. et al. Matrix crosslinking forces tumor progression by enhancing integrin signaling. Cell 139, 891–906 (2009). Presents compelling evidence drawing a correlation between tissue stiffness and breast cancer malignancy. Stiffening through the collagen crosslinking enzyme LOX leads to forced integrin clustering and focal adhesion formation and results in enhanced growth-factor signalling and breast cancer malignancy.

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Peng, L. et al. Whole genome expression analysis reveals differential effects of TiO2 nanotubes on vascular cells. Nano Lett. 10, 143–148 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Geblinger, D., Addadi, L. & Geiger, B. Nano-topography sensing by osteoclasts. J. Cell Sci. 123, 1503–1510 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Dalby, M. J., Riehle, M. O., Johnstone, H., Affrossman, S. & Curtis, A. S. In vitro reaction of endothelial cells to polymer demixed nanotopography. Biomaterials 23, 2945–2954 (2002).

    CAS  PubMed  Google Scholar 

  79. Cavalcanti-Adam, E. A. et al. Cell spreading and focal adhesion dynamics are regulated by spacing of integrin ligands. Biophys. J. 92, 2964–2974 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  80. Arnold, M. et al. Induction of cell polarization and migration by a gradient of nanoscale variations in adhesive ligand spacing. Nano Lett. 8, 2063–2069 (2008).

    CAS  PubMed  Google Scholar 

  81. Pelham, R. J. Jr & Wang, Y. Cell locomotion and focal adhesions are regulated by substrate flexibility. Proc. Natl Acad. Sci. USA 94, 13661–13665 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  82. Tan, W., Oldenburg, A. L., Norman, J. J., Desai, T. A. & Boppart, S. A. Optical coherence tomography of cell dynamics in three-dimensional tissue models. Opt. Express 14, 7159–7171 (2006).

    PubMed  Google Scholar 

  83. Friedl, P. & Brocker, E. B. The biology of cell locomotion within three-dimensional extracellular matrix. Cell. Mol. Life Sci. 57, 41–64 (2000).

    CAS  PubMed  Google Scholar 

  84. Doyle, A. D., Wang, F. W., Matsumoto, K. & Yamada, K. M. One-dimensional topography underlies three-dimensional fibrillar cell migration. J. Cell Biol. 184, 481–490 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Cukierman, E., Pankov, R., Stevens, D. R. & Yamada, K. M. Taking cell-matrix adhesions to the third dimension. Science 294, 1708–1712 (2001).

    CAS  PubMed  Google Scholar 

  86. Ochsner, M., Textor, M., Vogel, V. & Smith, M. L. Dimensionality controls cytoskeleton assembly and metabolism of fibroblast cells in response to rigidity and shape. PLoS ONE 5, e9445 (2010).

    PubMed  PubMed Central  Google Scholar 

  87. Wyckoff, J. B. et al. Direct visualization of macrophage-assisted tumor cell intravasation in mammary tumors. Cancer Res. 67, 2649–2656 (2007).

    CAS  PubMed  Google Scholar 

  88. Condeelis, J. & Pollard, J. W. Macrophages: obligate partners for tumor cell migration, invasion, and metastasis. Cell 124, 263–266 (2006).

    CAS  PubMed  Google Scholar 

  89. Wyckoff, J. B., Jones, J. G., Condeelis, J. S. & Segall, J. E. A critical step in metastasis: in vivo analysis of intravasation at the primary tumor. Cancer Res. 60, 2504–2511 (2000).

    CAS  PubMed  Google Scholar 

  90. Butcher, D. T., Alliston, T. & Weaver, V. M. A tense situation: forcing tumour progression. Nature Rev. Cancer 9, 108–122 (2009).

    CAS  PubMed  Google Scholar 

  91. Erler, J. T. et al. Hypoxia-induced lysyl oxidase is a critical mediator of bone marrow cell recruitment to form the premetastatic niche. Cancer Cell 15, 35–44 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  92. Ng, M. R. & Brugge, J. S. A stiff blow from the stroma: collagen crosslinking drives tumor progression. Cancer Cell 16, 455–457 (2009).

    CAS  PubMed  Google Scholar 

  93. Leung, C. T. & Brugge, J. S. Tumor self-seeding: bidirectional flow of tumor cells. Cell 139, 1226–1228 (2009).

    PubMed  Google Scholar 

  94. Avery, N. C. & Bailey, A. J. Enzymic and non-enzymic cross-linking mechanisms in relation to turnover of collagen: relevance to aging and exercise. Scand. J. Med. Sci. Sports 15, 231–240 (2005).

    CAS  PubMed  Google Scholar 

  95. Perentes, J. Y. et al. In vivo imaging of extracellular matrix remodeling by tumor-associated fibroblasts. Nature Methods 6, 143–145 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  96. Buehler, M. J. Nanomechanics of collagen fibrils under varying cross-link densities: atomistic and continuum studies. J. Mech. Behav. Biomed. Mater. 1, 59–67 (2008).

    PubMed  Google Scholar 

  97. Reiser, K., McCormick, R. J. & Rucker, R. B. Enzymic and non-enzymic cross-linking mechanisms in relation to turnover of collagen: relevance to aging and exercise. FASEB J. 6, 2439–2449 (1992).

    CAS  PubMed  Google Scholar 

  98. Kessenbrock, K., Plaks, V. & Werb, Z. Matrix metalloproteinases: regulators of the tumor microenvironment. Cell 141, 52–67 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  99. Gehler, S. et al. Filamin A–β1 integrin complex tunes epithelial cell response to matrix tension. Mol. Biol. Cell 20, 3224–3238 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Hattrup, C. L. & Gendler, S. J. Structure and function of the cell surface (tethered) mucins. Ann. Rev. Physiol. 70, 431–457 (2008).

    CAS  Google Scholar 

  101. Theocharis, A. D., Tsara, M. E., Papageorgacopoulou, N., Karavias, D. D. & Theocharis, D. A. Pancreatic carcinoma is characterized by elevated content of hyaluronan and chondroitin sulfate with altered disaccharide composition. Biochim. Biophys. Acta 1502, 201–206 (2000).

    CAS  PubMed  Google Scholar 

  102. Toole, B. P. Hyaluronan promotes the malignant phenotype. Glycobiology 12, 37R–42R (2002).

    CAS  PubMed  Google Scholar 

  103. Varga, I. et al. Expression of invasion-related extracellular matrix molecules in human glioblastoma versus intracerebral lung adenocarcinoma metastasis. Cen. Eur. Neurosurg. 71, 173–180 (2010).

    CAS  Google Scholar 

  104. Hynes, R. O. The extracellular matrix: not just pretty fibrils. Science 326, 1216–1219 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Lodish, H. et al. Molecular Cell Biology, 4th edition (W. H. Freeman, New York, 2000).

    Google Scholar 

  106. Wozniak, M. A. & Chen, C. S. Mechanotransduction in development: a growing role for contractility. Nature Rev. Mol. Cell Biol. 10, 34–43 (2009). An excellent review highlighting the general role of force and mechanotransduction in biology, centring on how contractility plays a role in development through regulating tissue structure and function.

    CAS  Google Scholar 

  107. Farge, E. Mechanical induction of twist in the Drosophila foregut/stomodeal primordium. Curr. Biol. 13, 1365–1377 (2003).

    CAS  PubMed  Google Scholar 

Download references

Acknowledgements

We apologize to all colleagues whose work cannot be cited owing to space limitations. This work was supported by the Breast Cancer Research Program of the US Department of Defense Era of Hope grant W81XWH-05-1-0330, US National Cancer Institute (NCI) grants U54CA143836-01, and US National Institutes of Health (NIH) NCI R01 CA138818-01A1 (to V.M.W.), as well as NIH NCI Breast Spore P50CA58207, which provided support for C.C.D.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Valerie M. Weaver.

Ethics declarations

Competing interests

The authors declare no competing financial interests.

Related links

Related links

FURTHER INFORMATION

Valerie M. Weaver's homepage

Glossary

Kartagener's syndrome

A developmental disorder in which a disruption to mechanotransduction signalling by cilia-driven fluid flow results in the mirror-image reversal of internal organs.

Hutchinson–Gilford progeria syndrome

A disorder that is characterized by the rapid and dramatic appearance of ageing. The disease results from a genetic condition in which an abnormal version of the lamin A protein is produced, resulting in a highly unstable nuclear envelope. This is hypothesized to result in a disruption to mechanotransduction in vascular cells, contributing to arteriosclerosis, the leading cause of death for patients with this disease.

Mechanotransduction

The process through which cells sense and respond to their mechanical environment, such as the extracellular matrix, adjacent cells or external stresses. During mechanotransduction, mechanical signals are sensed and activate intracellular biochemical signalling pathways.

Actomyosin

Actin is one of the principal components of the cytoskeleton and forms a network of filaments with a class of molecular motors called myosins. The actomyosin network is best known for its role in contractility and force generation.

Interstitial flow

Present in all living systems, this type of fluid flow produces small currents through tissues and the extracellular matrix and is driven by dynamic stress.

Transcellular

Whereas 'paracellular' delineates processes occurring between cells, transcellular describes processes occurring through cells. One example is in transcellular transport, where molecules are moved through an epithelial cell layer.

Epithelial–mesenchymal transitions

Instances of a developmental programme that is hypothesized to be activated in metastasis and proliferation. This transition is characterized by an enhanced migratory capacity, loss of cell adhesion, the downregulation of E-cadherin, and a malignant phenotype.

Stomodeal primordium

In Drosophila melanogaster, the stomodeal primordium separates the anterior midgut from the middle germ layer, the mesoderm.

Gastrulation

A developmental change that is characterized by a large-scale movement of cells, from which the embryo first begins to take shape, transitioning from a spherical mass of cells into an organized multilayered structure establishing the three primary germ layers.

Amnioserosa

An extraembryonic epithelial tissue present in Drosophila melanogaster that is required for dorsal closure.

Epiboly

Formally defined as a growing of one part over another, epiboly is a coordinated movement occurring during gastrulation that is characterized by the thinning and spreading of a multilayered cell sheet.

Radial intercalation

A tissue-rearrangement process during development in which the cells in the deep germ layers of a developing embryo move towards the outer layers.

Blastocoel

A fluid-filled cavity that the embryo develops as it forms. It is the central region of a blastocyst.

Glycocalyx

The carbohydrate-enriched coating, consisting of proteoglycans and glycoproteins, of the plasma membrane of eukaryotic, bacterial and archaeal cells. Ithas a number of functions, including roles in cell adhesion, mechanotransduction, vascular physiology, pathology, and guiding cell movement during development.

Rights and permissions

Reprints and Permissions

About this article

Cite this article

DuFort, C., Paszek, M. & Weaver, V. Balancing forces: architectural control of mechanotransduction. Nat Rev Mol Cell Biol 12, 308–319 (2011). https://doi.org/10.1038/nrm3112

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1038/nrm3112

Further reading

Search

Quick links

Nature Briefing

Sign up for the Nature Briefing newsletter — what matters in science, free to your inbox daily.

Get the most important science stories of the day, free in your inbox. Sign up for Nature Briefing