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  • Review Article
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Integrins as biomechanical sensors of the microenvironment

Abstract

Integrins, and integrin-mediated adhesions, have long been recognized to provide the main molecular link attaching cells to the extracellular matrix (ECM) and to serve as bidirectional hubs transmitting signals between cells and their environment. Recent evidence has shown that their combined biochemical and mechanical properties also allow integrins to sense, respond to and interact with ECM of differing properties with exquisite specificity. Here, we review this work first by providing an overview of how integrin function is regulated from both a biochemical and a mechanical perspective, affecting integrin cell-surface availability, binding properties, activation or clustering. Then, we address how this biomechanical regulation allows integrins to respond to different ECM physicochemical properties and signals, such as rigidity, composition and spatial distribution. Finally, we discuss the importance of this sensing for major cell functions by taking cell migration and cancer as examples.

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Fig. 1: Distinct levels of integrin regulation.
Fig. 2: Force regulates integrin properties.
Fig. 3: Integrins mediate response to extracellular matrix (ECM) signals such as force, rigidity and ligand distribution.
Fig. 4: Integrin-mediated regulation of cell migration.

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References

  1. Hynes, R. O. & Yamada, K. M. Fibronectins: multifunctional modular glycoproteins. J. Cell Biol. 95, 369–377 (1982).

    CAS  PubMed  Google Scholar 

  2. Hynes, R. O. The emergence of integrins: a personal and historical perspective. Matrix Biol. 23, 333–340 (2004).

    CAS  PubMed  PubMed Central  Google Scholar 

  3. Bissell, M. J., Hall, H. G. & Parry, G. How does the extracellular matrix direct gene expression? J. Theor. Biol. 99, 31–68 (1982).

    CAS  PubMed  Google Scholar 

  4. Winograd-Katz, S. E., Fassler, R., Geiger, B. & Legate, K. R. The integrin adhesome: from genes and proteins to human disease. Nat. Rev. Mol. Cell. Biol. 15, 273–288 (2014).

    CAS  PubMed  Google Scholar 

  5. Hamidi, H. & Ivaska, J. Every step of the way: integrins in cancer progression and metastasis. Nat. Rev. Cancer 18, 533–548 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  6. Humphries, J. D., Chastney, M. R., Askari, J. A. & Humphries, M. J. Signal transduction via integrin adhesion complexes. Curr. Opin. Cell Biol. 56, 14–21 (2018).

    PubMed  Google Scholar 

  7. De Franceschi, N., Hamidi, H., Alanko, J., Sahgal, P. & Ivaska, J. Integrin traffic — the update. J. Cell Sci. 128, 839–852 (2015).

    PubMed  PubMed Central  Google Scholar 

  8. Sun, Z., Guo, S. S. & Fassler, R. Integrin-mediated mechanotransduction. J. Cell Biol. 215, 445–456 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  9. Seetharaman, S. & Etienne-Manneville, S. Integrin diversity brings specificity in mechanotransduction. Biol. Cell 110, 49–64 (2018).

    CAS  PubMed  Google Scholar 

  10. Chen, Y., Ju, L., Rushdi, M., Ge, C. & Zhu, C. Receptor-mediated cell mechanosensing. Mol. Biol. Cell. 28, 3134–3155 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  11. Bouvard, D., Pouwels, J., De Franceschi, N. & Ivaska, J. Integrin inactivators: balancing cellular functions in vitro and in vivo. Nat. Rev. Mol. Cell. Biol. 14, 430–442 (2013).

    PubMed  Google Scholar 

  12. Hynes, R. O. Integrins: bidirectional, allosteric signaling machines. Cell 110, 673–687 (2002).

    CAS  PubMed  Google Scholar 

  13. Humphries, J. D., Byron, A. & Humphries, M. J. Integrin ligands at a glance. J. Cell Sci. 119, 3901–3903 (2006).

    CAS  PubMed  PubMed Central  Google Scholar 

  14. Tiwari, S., Askari, J. A., Humphries, M. J. & Bulleid, N. J. Divalent cations regulate the folding and activation status of integrins during their intracellular trafficking. J. Cell Sci. 124, 1672–1680 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  15. Heino, J., Ignotz, R. A., Hemler, M. E., Crouse, C. & Massagué, J. Regulation of cell adhesion receptors by transforming growth factor-beta. Concomitant regulation of integrins that share a common beta 1 subunit. J. Biol. Chem. 264, 380–388 (1989).

    CAS  PubMed  Google Scholar 

  16. Xiong, J.-P. et al. Crystal structure of the extracellular segment of integrin αVβ3 in complex with an Arg-Gly-Asp ligand. Science 296, 151–155 (2002).

    CAS  PubMed  Google Scholar 

  17. Takagi, J., Petre, B. M., Walz, T. & Springer, T. A. Global conformational rearrangements in integrin extracellular domains in outside-in and inside-out signaling. Cell 110, 599–611 (2002).

    CAS  PubMed  Google Scholar 

  18. Takagi, J., Strokovich, K., Springer, T. A. & Walz, T. Structure of integrin alpha5beta1 in complex with fibronectin. EMBO J. 22, 4607–4615 (2003).

    CAS  PubMed  PubMed Central  Google Scholar 

  19. Emsley, J., Knight, C. G., Farndale, R. W., Barnes, M. J. & Liddington, R. C. Structural basis of collagen recognition by integrin alpha2beta1. Cell 101, 47–56 (2000).

    CAS  PubMed  Google Scholar 

  20. Lee, J. O., Rieu, P., Arnaout, M. A. & Liddington, R. Crystal structure of the A domain from the alpha subunit of integrin CR3 (CD11b/CD18). Cell 80, 631–638 (1995).

    CAS  PubMed  Google Scholar 

  21. Ivaska, J. & Heino, J. Cooperation between integrins and growth factor receptors in signaling and endocytosis. Annu. Rev. Cell. Dev. Biol. 27, 291–320 (2011).

    CAS  PubMed  Google Scholar 

  22. Gasparski, A. N. & Beningo, K. A. Mechanoreception at the cell membrane: More than the integrins. Arch. Biochem. Biophys. 586, 20–26 (2015).

    CAS  PubMed  Google Scholar 

  23. Ramovs, V., Te Molder, L. & Sonnenberg, A. The opposing roles of laminin-binding integrins in cancer. Matrix Biol. 57–58, 213–243 (2017).

    PubMed  Google Scholar 

  24. Tadokoro, S. et al. Talin binding to integrin beta tails: a final common step in integrin activation. Science 302, 103–106 (2003).

    CAS  PubMed  Google Scholar 

  25. Shattil, S. J., Kim, C. & Ginsberg, M. H. The final steps of integrin activation: the end game. Nat. Rev. Mol. Cell Biol. 11, 288–300 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  26. Rognoni, E., Ruppert, R. & Fässler, R. The kindlin family: functions, signaling properties and implications for human disease. J. Cell. Sci. 129, 17–27 (2016).

    CAS  PubMed  Google Scholar 

  27. Böttcher, R. T. et al. Kindlin-2 recruits paxillin and Arp2/3 to promote membrane protrusions during initial cell spreading. J. Cell Biol. 216, 3785–3798 (2017).

    PubMed  PubMed Central  Google Scholar 

  28. Georgiadou, M. & Ivaska, J. Tensins: bridging AMP-activated protein kinase with integrin activation. Trends Cell Biol. 27, 703–711 (2017).

    CAS  PubMed  Google Scholar 

  29. Georgiadou, M. et al. AMPK negatively regulates tensin-dependent integrin activity. J. Cell Biol. 216, 1107–1121 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  30. McCleverty, C. J., Lin, D. C. & Liddington, R. C. Structure of the PTB domain of tensin1 and a model for its recruitment to fibrillar adhesions. Protein Sci. 16, 1223–1229 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  31. Bouin, A. P. et al. ICAP-1 monoubiquitylation coordinates matrix density and rigidity sensing for cell migration through ROCK2-MRCKalpha balance. J. Cell Sci. 130, 626–636 (2017).

    PubMed  Google Scholar 

  32. Rossier, O. et al. Integrins β1 and β3 exhibit distinct dynamic nanoscale organizations inside focal adhesions. Nat. Cell Biol. 14, 1231 (2012).

    CAS  Google Scholar 

  33. Lee, H.-S., Lim, C. J., Puzon-McLaughlin, W., Shattil, S. J. & Ginsberg, M. H. RIAM activates integrins by linking talin to Ras GTPase membrane-targeting sequences. J. Biol. Chem. 284, 5119–5127 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  34. Zhu, L. et al. Structure of Rap1b bound to talin reveals a pathway for triggering integrin activation. Nat. Commun. 8, 1744 (2017).

    PubMed  PubMed Central  Google Scholar 

  35. De Franceschi, N. et al. ProLIF — quantitative integrin protein-protein interactions and synergistic membrane effects on proteoliposomes. J. Cell. Sci. 132, jcs214270 (2018).

    PubMed  PubMed Central  Google Scholar 

  36. Lilja, J. et al. SHANK proteins limit integrin activation by directly interacting with Rap1 and R-Ras. Nat. Cell Biol. 19, 292–305 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  37. Horton, E. R. et al. Modulation of FAK and Src adhesion signaling occurs independently of adhesion complex composition. J. Cell Biol. 212, 349–364 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  38. Lawson, C. et al. FAK promotes recruitment of talin to nascent adhesions to control cell motility. J. Cell Biol. 196, 223–232 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  39. Horton, E. R. et al. Definition of a consensus integrin adhesome and its dynamics during adhesion complex assembly and disassembly. Nat. Cell Biol. 17, 1577–1587 (2015). In this article the authors provide a comprehensive analysis of published integrin ‘adhesome’ proteomic studies and curate a list of the ‘consensus adhesome’ proteins.

    CAS  PubMed  PubMed Central  Google Scholar 

  40. Alanko, J. et al. Integrin endosomal signalling suppresses anoikis. Nat. Cell Biol. 17, 1412–1421 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  41. Nader, G. P. F., Ezratty, E. J. & Gundersen, G. G. FAK, talin and PIPKIγ regulate endocytosed integrin activation to polarize focal adhesion assembly. Nat. Cell Biol. 18, 491–503 (2016).

    CAS  PubMed  Google Scholar 

  42. Shafaq-Zadah, M. et al. Persistent cell migration and adhesion rely on retrograde transport of β(1) integrin. Nat. Cell Biol. 18, 54–64 (2016).

    CAS  PubMed  Google Scholar 

  43. Paul, N. R., Jacquemet, G. & Caswell, P. T. Endocytic trafficking of integrins in cell migration. Curr. Biol. 25, R1092–R1105 (2015).

    CAS  PubMed  Google Scholar 

  44. Lobert, V. H. et al. Ubiquitination of alpha 5 beta 1 integrin controls fibroblast migration through lysosomal degradation of fibronectin-integrin complexes. Dev. Cell 19, 148–159 (2010).

    CAS  PubMed  Google Scholar 

  45. Steinberg, F., Heesom, K. J., Bass, M. D. & Cullen, P. J. SNX17 protects integrins from degradation by sorting between lysosomal and recycling pathways. J. Cell Biol. 197, 219–230 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  46. McNally, K. E. et al. Retriever is a multiprotein complex for retromer-independent endosomal cargo recycling. Nat. Cell Biol. 19, 1214–1225 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  47. Ratcliffe, C. D. H., Sahgal, P., Parachoniak, C. A., Ivaska, J. & Park, M. Regulation of cell migration and β1 integrin trafficking by the endosomal adaptor GGA3. Traffic 17, 670–688 (2016).

    CAS  PubMed  Google Scholar 

  48. Böttcher, R. T. et al. Sorting nexin 17 prevents lysosomal degradation of β1 integrins by binding to the β1-integrin tail. Nat. Cell Biol. 14, 584–592 (2012).

    PubMed  Google Scholar 

  49. Ezratty, E. J., Bertaux, C., Marcantonio, E. E. & Gundersen, G. G. Clathrin mediates integrin endocytosis for focal adhesion disassembly in migrating cells. J. Cell Biol. 187, 733–747 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  50. De Franceschi, N. et al. Selective integrin endocytosis is driven by interactions between the integrin α-chain and AP2. Nat. Struct. Mol. Biol. 23, 172–179 (2016).

    PubMed  PubMed Central  Google Scholar 

  51. Lakshminarayan, R. et al. Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers. Nat. Cell Biol. 16, 595–606 (2014).

    CAS  PubMed  Google Scholar 

  52. Moreno-Layseca, P., Icha, J., Hamidi, H. & Ivaska, J. Integrin trafficking in cells and tissues. Nat. Cell Biol. 21, 122–132 (2019).

    CAS  PubMed  PubMed Central  Google Scholar 

  53. Garcia-Manyes, S. & Beedle, A. E. M. Steering chemical reactions with force. Nat. Rev. Chem. 1, 0083 (2017).

    CAS  Google Scholar 

  54. Bell, G. I. Models for the specific adhesion of cells to cells. Science 200, 618–627 (1978).

    CAS  PubMed  Google Scholar 

  55. Rakshit, S. & Sivasankar, S. Biomechanics of cell adhesion: how force regulates the lifetime of adhesive bonds at the single molecule level. Phys. Chem. Chem. Phys. 16, 2211–2223 (2014).

    CAS  PubMed  Google Scholar 

  56. Suzuki, Y. & Dudko, O. K. Single-molecule rupture dynamics on multidimensional landscapes. Phys. Rev. Lett. 104, 048101 (2010).

    PubMed  Google Scholar 

  57. Kong, F., Garcia, A. J., Mould, A. P., Humphries, M. J. & Zhu, C. Demonstration of catch bonds between an integrin and its ligand. J. Cell Biol. 185, 1275–1284 (2009). This work was the first demonstration that integrin–ECM bonds can act as catch bonds.

    CAS  PubMed  PubMed Central  Google Scholar 

  58. Chen, Y., Lee, H., Tong, H., Schwartz, M. & Zhu, C. Force regulated conformational change of integrin αVβ3. Matrix Biol. 60–61, 70–85 (2016).

    PubMed  PubMed Central  Google Scholar 

  59. Elosegui-Artola, A. et al. Mechanical regulation of a molecular clutch defines force transmission and transduction in response to matrix rigidity. Nat. Cell Biol. 18, 540–548 (2016). This work shows that the differential effect of force on integrin–fibronectin unbinding (catch bond) and on talin unfolding (slip bond) leads to a mechanosensing mechanism, which allows talin unfolding only when cells are seeded on stiff substrates.

    CAS  PubMed  Google Scholar 

  60. Chen, W., Lou, J. & Zhu, C. Forcing switch from short- to intermediate- and long-lived states of the alphaA domain generates LFA-1/ICAM-1 catch bonds. J. Biol. Chem. 285, 35967–35978 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  61. Choi, Y. I. et al. Dynamic control of beta1 integrin adhesion by the plexinD1-sema3E axis. Proc. Natl Acad. Sci. USA 111, 379–384 (2014). This work provides an elegant example of mechanochemical coupling in integrins, showing that signalling events involving plexin D1 and semaphorin 3E regulate the mechanical properties (catch bond behaviour) of integrins.

    CAS  PubMed  Google Scholar 

  62. Rosetti, F. et al. A lupus-associated Mac-1 variant has defects in integrin allostery and interaction with ligands under force. Cell Rep. 10, 1655–1664 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  63. Friedland, J. C., Lee, M. H. & Boettiger, D. Mechanically activated integrin switch controls alpha(5)beta(1) function. Science 323, 642–644 (2009).

    CAS  PubMed  Google Scholar 

  64. Benito-Jardon, M. et al. The fibronectin synergy site re-enforces cell adhesion and mediates a crosstalk between integrin classes. eLife 6, e22264 (2017).

    PubMed  PubMed Central  Google Scholar 

  65. Zhu, J., Zhu, J. & Springer, T. A. Complete integrin headpiece opening in eight steps. J. Cell Biol. 201, 1053–1068 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  66. Chakrabarti, S., Hinczewski, M. & Thirumalai, D. Plasticity of hydrogen bond networks regulates mechanochemistry of cell adhesion complexes. Proc. Natl Acad. Sci. USA 111, 9048–9053 (2014).

    CAS  PubMed  Google Scholar 

  67. Chakrabarti, S., Hinczewski, M. & Thirumalai, D. Phenomenological and microscopic theories for catch bonds. J. Struct. Biol. 197, 50–56 (2017).

    CAS  PubMed  Google Scholar 

  68. Rakshit, S., Zhang, Y., Manibog, K., Shafraz, O. & Sivasankar, S. Ideal, catch, and slip bonds in cadherin adhesion. Proc. Natl Acad. Sci. USA 109, 18815–18820 (2012).

    CAS  PubMed  Google Scholar 

  69. Fennewald, S. M., Kantara, C., Sastry, S. K. & Resto, V. A. Laminin interactions with head and neck cancer cells under low fluid shear conditions lead to integrin activation and binding. J. Biol. Chem. 287, 21058–21066 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  70. Puklin-Faucher, E. & Vogel, V. Integrin activation dynamics between the RGD-binding site and the headpiece hinge. J. Biol. Chem. 284, 36557–36568 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  71. Zhu, J. et al. Structure of a complete integrin ectodomain in a physiologic resting state and activation and deactivation by applied forces. Mol. Cell 32, 849–861 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  72. Chen, W. et al. Molecular dynamics simulations of forced unbending of integrin alpha(v)beta(3). PLOS Comput. Biol. 7, e1001086 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  73. Chen, W., Lou, J., Evans, E. A. & Zhu, C. Observing force-regulated conformational changes and ligand dissociation from a single integrin on cells. J. Cell Biol. 199, 497–512 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  74. Comrie, W. A., Babich, A. & Burkhardt, J. K. F-Actin flow drives affinity maturation and spatial organization of LFA-1 at the immunological synapse. J. Cell Biol. 208, 475–491 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  75. Nordenfelt, P., Elliott, H. L. & Springer, T. A. Coordinated integrin activation by actin-dependent force during T cell migration. Nat. Commun. 7, 13119 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  76. Kong, F. et al. Cyclic mechanical reinforcement of integrin-ligand interactions. Mol. Cell 49, 1060–1068 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  77. Gonzalez-Tarrago, V. et al. Binding of ZO-1 to alpha5beta1 integrins regulates the mechanical properties of alpha5beta1-fibronectin links. Mol. Biol. Cell. 28, 1847–1852 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  78. Li, J. & Springer, T. A. Integrin extension enables ultrasensitive regulation by cytoskeletal force. Proc. Natl Acad. Sci. USA 114, 4685–4690 (2017).

    CAS  PubMed  Google Scholar 

  79. Shemesh, T., Geiger, B., Bershadsky, A. D. & Kozlov, M. M. Focal adhesions as mechanosensors: a physical mechanism. Proc. Natl Acad. Sci. USA 102, 12383–12388 (2005).

    CAS  PubMed  Google Scholar 

  80. Cao, X. et al. A chemomechanical model of matrix and nuclear rigidity regulation of focal adhesion size. Biophys. J. 109, 1807–1817 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  81. Chaudhuri, O. et al. Extracellular matrix stiffness and composition jointly regulate the induction of malignant phenotypes in mammary epithelium. Nat. Mater. 13, 970–978 (2014).

    CAS  PubMed  Google Scholar 

  82. 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 

  83. Paszek, M. J. et al. The cancer glycocalyx mechanically primes integrin-mediated growth and survival. Nature 511, 319–325 (2014). This work shows that repulsive steric forces from the glycocalyx are transmitted to integrins, leading to mechanotransduction and cell growth, with implications in cancer.

    CAS  PubMed  PubMed Central  Google Scholar 

  84. Eng, E. T., Smagghe, B. J., Walz, T. & Springer, T. A. Intact αIIbβ3 integrin is extended after activation as measured by solution X-ray scattering and electron microscopy. J. Biol. Chem. 286, 35218–35226 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  85. Bucher, D. et al. Clathrin-adaptor ratio and membrane tension regulate the flat-to-curved transition of the clathrin coat during endocytosis. Nat. Commun. 9, 1109 (2018).

    PubMed  PubMed Central  Google Scholar 

  86. Thottacherry, J. J. et al. Mechanochemical feedback control of dynamin independent endocytosis modulates membrane tension in adherent cells. Nat. Commun. 9, 4217 (2018). The authors of this study demonstrate that endocytosis through the CLIC/GEEC pathway is increased by lower membrane tension triggered by loss of cell adhesion.

    PubMed  PubMed Central  Google Scholar 

  87. Holst, M. R. et al. Clathrin-independent endocytosis suppresses cancer cell blebbing and invasion. Cell Rep. 20, 1893–1905 (2017).

    CAS  PubMed  Google Scholar 

  88. Yu, C.-h et al. Integrin-beta3 clusters recruit clathrin-mediated endocytic machinery in the absence of traction force. Nat. Commun. 6, 8672 (2015). The authors demonstrate, using lipid-bilayer or glass-coupled RGD ligands, that loss of traction force induces recruitment of clathrin adaptors and endocytosis of β3 integrins but not β1 integrins.

    CAS  PubMed  PubMed Central  Google Scholar 

  89. Schiller, H. B. et al. beta1- and alphav-class integrins cooperate to regulate myosin II during rigidity sensing of fibronectin-based microenvironments. Nat. Cell Biol. 15, 625–636 (2013).

    CAS  PubMed  Google Scholar 

  90. Du, J. et al. Integrin activation and internalization on soft ECM as a mechanism of induction of stem cell differentiation by ECM elasticity. Proc. Natl Acad. Sci. USA 108, 9466–9471 (2011).

    CAS  PubMed  Google Scholar 

  91. Elosegui-Artola, A., Trepat, X. & Roca-Cusachs, P. Control of mechanotransduction by molecular clutch dynamics. Trends Cell Biol. 28, 356–367 (2018).

    CAS  PubMed  Google Scholar 

  92. Roca-Cusachs, P., Conte, V. & Trepat, X. Quantifying forces in cell biology. Nat. Cell Biol. 19, 742–751 (2017).

    CAS  PubMed  Google Scholar 

  93. Humphrey, J. D., Schwartz, M. A., Tellides, G. & Milewicz, D. M. Role of mechanotransduction in vascular biology: focus on thoracic aortic aneurysms and dissections. Circ. Res. 116, 1448–1461 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  94. Waters, C. M., Roan, E. & Navajas, D. Mechanobiology in lung epithelial cells: measurements, perturbations, and responses. Compr. Physiol. 2, 1–29 (2012).

    PubMed  PubMed Central  Google Scholar 

  95. Paszek, M. J. & Weaver, V. M. The tension mounts: mechanics meets morphogenesis and malignancy. J. Mammary Gland Biol. Neoplasia 9, 325–342 (2004).

    PubMed  Google Scholar 

  96. Bross, S., Braun, P. M., Michel, M. S., Juenemann, K. P. & Alken, P. Bladder wall tension during physiological voiding and in patients with an unstable detrusor or bladder outlet obstruction. BJU Int. 92, 584–588 (2003).

    CAS  PubMed  Google Scholar 

  97. DuFort, C. C., Paszek, M. J. & Weaver, V. M. Balancing forces: architectural control of mechanotransduction. Nat. Rev. Mol. Cell. Biol. 12, 308–319 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  98. Schedin, P. & Keely, P. J. Mammary gland ECM remodeling, stiffness, and mechanosignaling in normal development and tumor progression. Cold Spring Harb. Perspect. Biol. 3, a003228 (2011).

    PubMed  PubMed Central  Google Scholar 

  99. Northey, J. J., Przybyla, L. & Weaver, V. M. Tissue force programs cell fate and tumor aggression. Cancer Discov. 7, 1224–1237 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  100. Morimatsu, M., Mekhdjian, A. H., Adhikari, A. S. & Dunn, A. R. Molecular tension sensors report forces generated by single integrin molecules in living cells. Nano Lett. 13, 3985–3989 (2013). In this work, the authors developed a Förster resonance energy transfer probe to measure integrin forces at the single-molecule level, which proved to be highly heterogeneous and of the order of a few piconewtons.

    CAS  PubMed  Google Scholar 

  101. Zhang, Y., Ge, C., Zhu, C. & Salaita, K. DNA-based digital tension probes reveal integrin forces during early cell adhesion. Nat. Commun. 5, 5167 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  102. Blakely, B. L. et al. A DNA-based molecular probe for optically reporting cellular traction forces. Nat. Methods 11, 1229–1232 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  103. Chang, A. C. et al. Single molecule force measurements in living cells reveal a minimally tensioned integrin state. ACS Nano 10, 10745–10752 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  104. Wang, X. & Ha, T. Defining single molecular forces required to activate integrin and Notch signaling. Science 340, 991–994 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  105. Rahil, Z. et al. Nanoscale mechanics guides cellular decision making. Integr. Biol. 8, 929–935 (2016).

    CAS  Google Scholar 

  106. Galior, K., Liu, Y., Yehl, K., Vivek, S. & Salaita, K. Titin-based nanoparticle tension sensors map high-magnitude integrin forces within focal adhesions. Nano Lett. 16, 341–348 (2016). By developing a sensor based on fluorescence quenching, the authors found that single integrin forces can reach values exceding 100 pN.

    CAS  PubMed  Google Scholar 

  107. Zhang, Y. et al. Platelet integrins exhibit anisotropic mechanosensing and harness piconewton forces to mediate platelet aggregation. Proc. Natl Acad. Sci. USA 115, 325–330 (2018).

    CAS  PubMed  Google Scholar 

  108. Roca-Cusachs, P., Gauthier, N. C., del Rio, A. & Sheetz, M. P. Clustering of α5β1 integrins determines adhesion strength whereas αvβ3 and talin enable mechanotransduction. Proc. Natl Acad. Sci. USA 106, 16245–16250 (2009).

    CAS  PubMed  Google Scholar 

  109. Roca-Cusachs, P. et al. Integrin-dependent force transmission to the extracellular matrix by alpha-actinin triggers adhesion maturation. Proc. Natl Acad. Sci. USA 110, E1361–E1370 (2013).

    CAS  PubMed  Google Scholar 

  110. Jiang, G. Y., Giannone, G., Critchley, D. R., Fukumoto, E. & Sheetz, M. P. Two-piconewton slip bond between fibronectin and the cytoskeleton depends on talin. Nature 424, 334–337 (2003).

    CAS  PubMed  Google Scholar 

  111. Strohmeyer, N., Bharadwaj, M., Costell, M., Fassler, R. & Muller, D. J. Fibronectin-bound alpha5beta1 integrins sense load and signal to reinforce adhesion in less than a second. Nat. Mater. 16, 1262–1270 (2017). This work shows that integrin-mediated reinforcement of adhesion takes place at the sub-second scale, and characterizes the molecular machinery involved.

    CAS  PubMed  Google Scholar 

  112. Riveline, D. et al. 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, 1175–1185 (2001).

    CAS  PubMed  PubMed Central  Google Scholar 

  113. 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 

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

    CAS  PubMed  Google Scholar 

  115. Hirata, H., Sokabe, M. & Lim, C. T. Molecular mechanisms underlying the force-dependent regulation of actin-to-ECM linkage at the focal adhesions. Prog. Mol. Biol. Transl Sci. 126, 135–154 (2014).

    CAS  PubMed  Google Scholar 

  116. Schiller, H. B. & Fassler, R. Mechanosensitivity and compositional dynamics of cell-matrix adhesions. EMBO Rep. 14, 509–519 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  117. Changede, R., Xu, X., Margadant, F. & Sheetz, M. P. Nascent integrin adhesions form on all matrix rigidities after integrin activation. Dev. Cell 35, 614–621 (2015). By developing a system of cell adhesion on fluid lipid bilayers, the authors elegantly decoupled initial formation of nascent adhesions (which is independent of force and rigidity) and subsequent maturation.

    CAS  PubMed  Google Scholar 

  118. Elosegui-Artola, A. et al. Rigidity sensing and adaptation through regulation of integrin types. Nat. Mater. 13, 631–637 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  119. Brockman, J. M. et al. Mapping the 3D orientation of piconewton integrin traction forces. Nat. Methods 15, 115–118 (2018).

    CAS  PubMed  Google Scholar 

  120. Swaminathan, V. et al. Actin retrograde flow actively aligns and orients ligand-engaged integrins in focal adhesions. Proc. Natl Acad. Sci. USA 114, 10648–10653 (2017). The authors describe that activated αvβ3 integrins are aligned with one another in focal adhesions in migrating cells and suggest this as a key mechanism underlying the ability of integrin-mediated adhesions to sense directional forces in their environment.

    CAS  PubMed  Google Scholar 

  121. Nordenfelt, P. et al. Direction of actin flow dictates integrin LFA-1 orientation during leukocyte migration. Nat. Commun. 8, 2047 (2017).

    PubMed  PubMed Central  Google Scholar 

  122. del Rio, A. et al. Stretching single talin rod molecules activates vinculin binding. Science 323, 638–641 (2009).

    PubMed  Google Scholar 

  123. Yao, M. et al. Mechanical activation of vinculin binding to talin locks talin in an unfolded conformation. Sci. Rep. 4, 4610 (2014).

    PubMed  PubMed Central  Google Scholar 

  124. Zhang, X. et al. Talin depletion reveals independence of initial cell spreading from integrin activation and traction. Nat. Cell Biol. 10, 1062–1068 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  125. Bharadwaj, M. et al. alphaV-class integrins exert dual roles on alpha5beta1 integrins to strengthen adhesion to fibronectin. Nat. Commun. 8, 14348 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  126. Balcioglu, H. E., van Hoorn, H., Donato, D. M., Schmidt, T. & Danen, E. H. The integrin expression profile modulates orientation and dynamics of force transmission at cell-matrix adhesions. J. Cell Sci. 128, 1316–1326 (2015).

    CAS  PubMed  Google Scholar 

  127. Seong, J. et al. Distinct biophysical mechanisms of focal adhesion kinase mechanoactivation by different extracellular matrix proteins. Proc. Natl Acad. Sci. USA 110, 19372–19377 (2013).

    CAS  PubMed  Google Scholar 

  128. Stricker, J., Aratyn-Schaus, Y., Oakes, P. W. & Gardel, M. L. Spatiotemporal constraints on the force-dependent growth of focal adhesions. Biophys. J. 100, 2883–2893 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  129. Oria, R. et al. Force loading explains spatial sensing of ligands by cells. Nature 552, 219–224 (2017). This work shows that cells can sense the distribution of integrin ECM ligands through differences in the force experienced by individual integrins.

    CAS  PubMed  Google Scholar 

  130. Choi, C. K. et al. Actin and alpha-actinin orchestrate the assembly and maturation of nascent adhesions in a myosin II motor-independent manner. Nat. Cell Biol. 10, 1039–1050 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  131. Oakes, P. W., Beckham, Y., Stricker, J. & Gardel, M. L. Tension is required but not sufficient for focal adhesion maturation without a stress fiber template. J. Cell Biol. 196, 363–374 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  132. Oakes, P. W. et al. Lamellipodium is a myosin-independent mechanosensor. Proc. Natl Acad. Sci. USA 115, 2646–2651 (2018).

    CAS  PubMed  Google Scholar 

  133. Pasapera, A. M., Schneider, I. C., Rericha, E., Schlaepfer, D. D. & Waterman, C. M. Myosin II activity regulates vinculin recruitment to focal adhesions through FAK-mediated paxillin phosphorylation. J. Cell Biol. 188, 877–890 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  134. Plotnikov, S. V., Pasapera, A. M., Sabass, B. & Waterman, C. M. Force fluctuations within focal adhesions mediate ECM-rigidity sensing to guide directed cell migration. Cell 151, 1513–1527 (2012).

    CAS  PubMed  Google Scholar 

  135. Guilluy, C. et al. The Rho GEFs LARG and GEF-H1 regulate the mechanical response to force on integrins. Nat. Cell Biol. 13, 722–727 (2011).

    PubMed  PubMed Central  Google Scholar 

  136. Pawlowski, R., Rajakyla, E. K., Vartiainen, M. K. & Treisman, R. An actin-regulated importin alpha/beta-dependent extended bipartite NLS directs nuclear import of MRTF-A. EMBO J. 29, 3448–3458 (2010).

    PubMed  PubMed Central  Google Scholar 

  137. Chang, L. et al. The SWI/SNF complex is a mechanoregulated inhibitor of YAP and TAZ. Nature 563, 265–269 (2018).

    CAS  PubMed  Google Scholar 

  138. Kirby, T. J. & Lammerding, J. Emerging views of the nucleus as a cellular mechanosensor. Nat. Cell Biol. 20, 373–381 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  139. Elosegui-Artola, A. et al. Force triggers YAP nuclear entry by regulating transport across nuclear pores. Cell 171, 1397–1410 (2017).

    CAS  PubMed  Google Scholar 

  140. Tajik, A. et al. Transcription upregulation via force-induced direct stretching of chromatin. Nat. Mater. 15, 1287–1296 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  141. Swift, J. et al. Nuclear lamin-A scales with tissue stiffness and enhances matrix-directed differentiation. Science 341, 1240104 (2013).

    PubMed  PubMed Central  Google Scholar 

  142. Ihalainen, T. O. et al. Differential basal-to-apical accessibility of lamin A/C epitopes in the nuclear lamina regulated by changes in cytoskeletal tension. Nat. Mater. 14, 1252–1261 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Guilluy, C. et al. Isolated nuclei adapt to force and reveal a mechanotransduction pathway in the nucleus. Nat. Cell Biol. 16, 376–381 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  144. Uhler, C. & Shivashankar, G. V. Regulation of genome organization and gene expression by nuclear mechanotransduction. Nat. Rev. Mol. Cell Biol. 18, 717 (2017).

    CAS  PubMed  Google Scholar 

  145. Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15, 786 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

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

    CAS  PubMed  PubMed Central  Google Scholar 

  147. Handorf, A. M., Zhou, Y., Halanski, M. A. & Li, W. J. Tissue stiffness dictates development, homeostasis, and disease progression. Organogenesis 11, 1–15 (2015).

    PubMed  PubMed Central  Google Scholar 

  148. Barriga, E. H., Franze, K., Charras, G. & Mayor, R. Tissue stiffening coordinates morphogenesis by triggering collective cell migration in vivo. Nature 554, 523–527 (2018). The authors demonstrate elegantly that changes in substrate stiffness can coordinate morphogenesis by triggering collective cell migration and promoting EMT in vivo.

    CAS  PubMed  PubMed Central  Google Scholar 

  149. Faurobert, E., Bouin, A. P. & Albiges-Rizo, C. Microenvironment, tumor cell plasticity, and cancer. Curr. Opin. Oncol. 27, 64–70 (2015).

    CAS  PubMed  Google Scholar 

  150. Wu, Z., Plotnikov, S. V., Moalim, A. Y., Waterman, C. M. & Liu, J. Two distinct actin networks mediate traction oscillations to confer focal adhesion mechanosensing. Biophys. J. 112, 780–794 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  151. Wolfenson, H. et al. Tropomyosin controls sarcomere-like contractions for rigidity sensing and suppressing growth on soft matrices. Nat. Cell Biol. 18, 33–42 (2016).

    CAS  PubMed  Google Scholar 

  152. Ghassemi, S. et al. Cells test substrate rigidity by local contractions on sub-micrometer pillars. Proc. Natl Acad. Sci. USA 109, 5328–5333 (2012).

    CAS  PubMed  Google Scholar 

  153. Meacci, G. et al. alpha-actinin links ECM rigidity sensing contractile units with periodic cell edge retractions. Mol. Biol. Cell. 27, 3471–3479 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  154. Chaudhuri, O. et al. Substrate stress relaxation regulates cell spreading. Nat. Commun. 6, 6364 (2015).

    PubMed  PubMed Central  Google Scholar 

  155. Wisdom, K. M. et al. Matrix mechanical plasticity regulates cancer cell migration through confining microenvironments. Nat. Commun. 9, 4144 (2018).

    PubMed  PubMed Central  Google Scholar 

  156. Gong, Z. et al. Matching material and cellular timescales maximizes cell spreading on viscoelastic substrates. Proc. Natl Acad. Sci. USA 115, E2686–E2695 (2018).

    CAS  PubMed  Google Scholar 

  157. Bennett, M. et al. Molecular clutch drives cell response to surface viscosity. Proc. Natl Acad. Sci. USA 115, 1192–1997 (2018).

    CAS  PubMed  Google Scholar 

  158. Gross, J. & Nagai, Y. Specific degradation of the collagen molecule by tadpole collagenolytic enzyme. Proc. Natl Acad. Sci. USA 54, 1197–1204 (1965).

    CAS  PubMed  Google Scholar 

  159. Stark, M. & Kühn, K. The properties of molecular fragments obtained on treating calfskin collagen with collagenase from Clostridium histolyticum. Eur. J. Biochem. 6, 534–541 (1968).

    CAS  PubMed  Google Scholar 

  160. Taubenberger, A. V., Woodruff, M. A., Bai, H., Muller, D. J. & Hutmacher, D. W. The effect of unlocking RGD-motifs in collagen I on pre-osteoblast adhesion and differentiation. Biomaterials 31, 2827–2835 (2010).

    CAS  PubMed  Google Scholar 

  161. Ortiz Franyuti, D., Mitsi, M. & Vogel, V. Mechanical stretching of fibronectin fibers upregulates binding of interleukin-7. Nano Lett. 18, 15–25 (2018).

    CAS  PubMed  Google Scholar 

  162. Deng, Z. J., Liang, M., Monteiro, M., Toth, I. & Minchin, R. F. Nanoparticle-induced unfolding of fibrinogen promotes Mac-1 receptor activation and inflammation. Nat. Nanotechnol. 6, 39–44 (2011).

    CAS  PubMed  Google Scholar 

  163. Roca-Cusachs, P., Iskratsch, T. & Sheetz, M. P. Finding the weakest link — exploring integrin-mediated mechanical molecular pathways. J. Cell Sci. 125, 3025–3038 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  164. Arnold, M. et al. Activation of integrin function by nanopatterned adhesive interfaces. Chemphyschem 5, 383–388 (2004).

    CAS  PubMed  Google Scholar 

  165. Cavalcanti-Adam, E. A. et al. Lateral spacing of integrin ligands influences cell spreading and focal adhesion assembly. Eur. J. Cell Biol. 85, 219–224 (2006).

    CAS  PubMed  Google Scholar 

  166. Altrock, E., Muth, C. A., Klein, G., Spatz, J. P. & Lee-Thedieck, C. The significance of integrin ligand nanopatterning on lipid raft clustering in hematopoietic stem cells. Biomaterials 33, 3107–3118 (2012).

    CAS  PubMed  Google Scholar 

  167. Amschler, K., Erpenbeck, L., Kruss, S. & Schon, M. P. Nanoscale integrin ligand patterns determine melanoma cell behavior. ACS Nano 8, 9113–9125 (2014).

    CAS  PubMed  Google Scholar 

  168. 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 

  169. Huang, J. et al. Impact of order and disorder in RGD nanopatterns on cell adhesion. Nano Lett. 9, 1111–1116 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  170. Schvartzman, M. et al. Nanolithographic control of the spatial organization of cellular adhesion receptors at the single-molecule level. Nano Lett. 11, 1306–1312 (2011).

    CAS  PubMed  PubMed Central  Google Scholar 

  171. Liu, Y. et al. Nanoparticle tension probes patterned at the nanoscale: impact of integrin clustering on force transmission. Nano Lett. 14, 5539–5546 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  172. Wipff, P. J., Rifkin, D. B., Meister, J. J. & Hinz, B. Myofibroblast contraction activates latent TGF-beta1 from the extracellular matrix. J. Cell Biol. 179, 1311–1323 (2007).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Sarrazy, V. et al. Integrins alphavbeta5 and alphavbeta3 promote latent TGF-beta1 activation by human cardiac fibroblast contraction. Cardiovasc. Res. 102, 407–417 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  174. Haeger, A., Wolf, K., Zegers, M. M. & Friedl, P. Collective cell migration: guidance principles and hierarchies. Trends Cell Biol. 25, 556–566 (2015).

    PubMed  Google Scholar 

  175. 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 

  176. Bangasser, B. L. et al. Shifting the optimal stiffness for cell migration. Nat. Commun. 8, 15313 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  177. Sunyer, R. et al. Collective cell durotaxis emerges from long-range intercellular force transmission. Science 353, 1157–1161 (2016).

    CAS  PubMed  Google Scholar 

  178. Monaghan, P., Warburton, M. J., Perusinghe, N. & Rudland, P. S. Topographical arrangement of basement membrane proteins in lactating rat mammary gland: comparison of the distribution of type IV collagen, laminin, fibronectin, and Thy-1 at the ultrastructural level. Proc. Natl Acad. Sci. USA 80, 3344–3348 (1983).

    CAS  PubMed  Google Scholar 

  179. Ingman, W. V., Wyckoff, J., Gouon-Evans, V., Condeelis, J. & Pollard, J. W. Macrophages promote collagen fibrillogenesis around terminal end buds of the developing mammary gland. Dev. Dyn. 235, 3222–3229 (2006).

    CAS  PubMed  Google Scholar 

  180. Peuhu, E. et al. SHARPIN regulates collagen architecture and ductal outgrowth in the developing mouse mammary gland. EMBO J. 36, 165–182 (2017). This work shows that regulation of integrin activation through SHARPIN affects tissue stiffness and cell migration in the mammary epithelium.

    CAS  PubMed  Google Scholar 

  181. Brownfield, D. G. et al. Patterned collagen fibers orient branching mammary epithelium through distinct signaling modules. Curr. Biol. 23, 703–709 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  182. Lopez, J. I., Kang, I., You, W.-K., McDonald, D. M. & Weaver, V. M. In situ force mapping of mammary gland transformation. Integr. Biol. 3, 910–921 (2011).

    CAS  Google Scholar 

  183. Conklin, M. W. et al. Aligned collagen is a prognostic signature for survival in human breast carcinoma. Am. J. Pathol. 178, 1221–1232 (2011). The authors demonstrate that the tumour-associated alignment and orientation of collagen fibres in the stroma of breast cancer tumours correlates with clinically poor patient outcome. Their data indicate that collagen alignment is a biomarker for the prediction of human breast cancer survival.

    PubMed  PubMed Central  Google Scholar 

  184. Sauka-Spengler, T. & Bronner-Fraser, M. A gene regulatory network orchestrates neural crest formation. Nat. Rev. Mol. Cell. Biol. 9, 557–568 (2008).

    CAS  PubMed  Google Scholar 

  185. Kerosuo, L. & Bronner-Fraser, M. What’s bad in cancer is good in the embryo: Importance of EMT in neural crest development. Semin. Cell Dev. Biol. 23, 320–332 (2012).

    CAS  PubMed  PubMed Central  Google Scholar 

  186. Naba, A. et al. The matrisome: in silico definition and in vivo characterization by proteomics of normal and tumor extracellular matrices. Mol. Cell. Proteomics 11, M111.014647 (2012).

    PubMed  Google Scholar 

  187. Friedl, P. & Alexander, S. Cancer invasion and the microenvironment: plasticity and reciprocity. Cell 147, 992–1009 (2011).

    CAS  PubMed  Google Scholar 

  188. McDonald, J. A., Kelley, D. G. & Broekelmann, T. J. Role of fibronectin in collagen deposition: Fab’ to the gelatin-binding domain of fibronectin inhibits both fibronectin and collagen organization in fibroblast extracellular matrix. J. Cell Biol. 92, 485–492 (1982).

    CAS  PubMed  Google Scholar 

  189. Lemmon, C. A., Chen, C. S. & Romer, L. H. Cell traction forces direct fibronectin matrix assembly. Biophys. J. 96, 729–738 (2009).

    CAS  PubMed  PubMed Central  Google Scholar 

  190. Oudin, M. J. & Weaver, V. M. Physical and chemical gradients in the tumor microenvironment regulate tumor cell invasion, migration, and metastasis. Cold Spring Harb. Symp. Quant. Biol. 81, 189–205 (2016).

    PubMed  Google Scholar 

  191. Barbazán, J. & Matic Vignjevic, D. Cancer associated fibroblasts: is the force the path to the dark side? Curr. Opin. Cell Biol. 56, 71–79 (2018).

    PubMed  Google Scholar 

  192. Totaro, A., Panciera, T. & Piccolo, S. YAP/TAZ upstream signals and downstream responses. Nat. Cell Biol. 20, 888–899 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  193. De Wever, O. et al. Tenascin-C and SF/HGF produced by myofibroblasts in vitro provide convergent pro-invasive signals to human colon cancer cells through RhoA and Rac. FASEB J. 18, 1016–1018 (2004).

    PubMed  Google Scholar 

  194. Oudin, M. J. et al. Tumor cell-driven extracellular matrix remodeling drives haptotaxis during metastatic progression. Cancer Discov. 6, 516–531 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  195. Erdogan, B. et al. Cancer-associated fibroblasts promote directional cancer cell migration by aligning fibronectin. J. Cell Biol. 216, 3799–3816 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  196. Attieh, Y. et al. Cancer-associated fibroblasts lead tumor invasion through integrin-beta3-dependent fibronectin assembly. J. Cell Biol. 216, 3509–3520 (2017).

    CAS  PubMed  PubMed Central  Google Scholar 

  197. Castro-Castro, A. et al. Cellular and molecular mechanisms of MT1-MMP-dependent cancer cell invasion. Annu. Rev. Cell Dev. Biol. 32, 555–576 (2016).

    CAS  PubMed  Google Scholar 

  198. Glentis, A. et al. Cancer-associated fibroblasts induce metalloprotease-independent cancer cell invasion of the basement membrane. Nat. Commun. 8, 924 (2017).

    PubMed  PubMed Central  Google Scholar 

  199. Lee, J. L. & Streuli, C. H. Integrins and epithelial cell polarity. J. Cell. Sci. 127, 3217–3225 (2014).

    CAS  PubMed  PubMed Central  Google Scholar 

  200. Yang, J. et al. Twist, a master regulator of morphogenesis, plays an essential role in tumor metastasis. Cell 117, 927–939 (2004).

    CAS  PubMed  Google Scholar 

  201. Xu, Y. et al. Twist1 promotes breast cancer invasion and metastasis by silencing Foxa1 expression. Oncogene 36, 1157–1166 (2017).

    CAS  PubMed  Google Scholar 

  202. Yang, J. et al. Twist induces epithelial-mesenchymal transition and cell motility in breast cancer via ITGB1-FAK/ILK signaling axis and its associated downstream network. Int. J. Biochem. Cell Biol. 71, 62–71 (2016).

    CAS  PubMed  Google Scholar 

  203. Sirka, O. K., Shamir, E. R. & Ewald, A. J. Myoepithelial cells are a dynamic barrier to epithelial dissemination. J. Cell Biol. 217, 3368–3381 (2018).

    CAS  PubMed  PubMed Central  Google Scholar 

  204. Wei, S. C. et al. Matrix stiffness drives epithelial-mesenchymal transition and tumour metastasis through a TWIST1-G3BP2 mechanotransduction pathway. Nat. Cell Biol. 17, 678–688 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  205. Shibue, T., Brooks, M. W. & Weinberg, R. A. An integrin-linked machinery of cytoskeletal regulation that enables experimental tumor initiation and metastatic colonization. Cancer Cell 24, 481–498 (2013).

    CAS  PubMed  Google Scholar 

  206. Chaurasia, P. et al. A region in urokinase plasminogen receptor domain III controlling a functional association with alpha5beta1 integrin and tumor growth. J. Biol. Chem. 281, 14852–14863 (2006).

    CAS  PubMed  Google Scholar 

  207. Barkan, D. et al. Metastatic growth from dormant cells induced by a col-I-enriched fibrotic environment. Cancer Res. 70, 5706–5716 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  208. Barkan, D. et al. Inhibition of metastatic outgrowth from single dormant tumor cells by targeting the cytoskeleton. Cancer Res. 68, 6241–6250 (2008).

    CAS  PubMed  PubMed Central  Google Scholar 

  209. Weaver, V. M. et al. Reversion of the malignant phenotype of human breast cells in three-dimensional culture and in vivo by integrin blocking antibodies. J. Cell Biol. 137, 231–245 (1997).

    CAS  PubMed  PubMed Central  Google Scholar 

  210. Albrengues, J. et al. Neutrophil extracellular traps produced during inflammation awaken dormant cancer cells in mice. Science 361, eaao4227 (2018).

    PubMed  PubMed Central  Google Scholar 

  211. Reynolds, A. R. et al. Stimulation of tumor growth and angiogenesis by low concentrations of RGD-mimetic integrin inhibitors. Nat. Med. 15, 392 (2009).

    CAS  PubMed  Google Scholar 

  212. Cavallaro, U. & Christofori, G. Cell adhesion in tumor invasion and metastasis: loss of the glue is not enough. Biochim. Biophys. Acta 1552, 39–45 (2001).

    CAS  PubMed  Google Scholar 

  213. Austen, K. et al. Extracellular rigidity sensing by talin isoform-specific mechanical linkages. Nat. Cell Biol. 17, 1597–1606 (2015).

    CAS  PubMed  PubMed Central  Google Scholar 

  214. Kumar, A. et al. Talin tension sensor reveals novel features of focal adhesion force transmission and mechanosensitivity. J. Cell Biol. 213, 371–383 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  215. Grashoff, C. et al. Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature 466, 263–266 (2010).

    CAS  PubMed  PubMed Central  Google Scholar 

  216. Lin, C.-H. & Forscher, P. Growth cone advance is inversely proportional to retrograde F-actin flow. Neuron 14, 763–771 (1995).

    CAS  PubMed  Google Scholar 

  217. Forscher, P. & Smith, S. J. Actions of cytochalasins on the organization of actin filaments and microtubules in a neuronal growth cone. J. Cell Biol. 107, 1505–1516 (1988).

    CAS  PubMed  Google Scholar 

  218. Wang, Y. L. Exchange of actin subunits at the leading edge of living fibroblasts: possible role of treadmilling. J. Cell Biol. 101, 597–602 (1985).

    CAS  PubMed  Google Scholar 

  219. Theriot, J. A. & Mitchison, T. J. Actin microfilament dynamics in locomoting cells. Nature 352, 126–131 (1991).

    CAS  PubMed  Google Scholar 

  220. Hu, K., Ji, L., Applegate, K. T., Danuser, G. & Waterman-Storer, C. M. Differential transmission of actin motion within focal adhesions. Science 315, 111–115 (2007).

    CAS  PubMed  Google Scholar 

  221. Eisenberg, E., Hill, T. L. & Chen, Y. Cross-bridge model of muscle contraction. Quantitative analysis. Biophys. J. 29, 195–227 (1980).

    CAS  PubMed  Google Scholar 

  222. Chan, C. E. & Odde, D. J. Traction dynamics of filopodia on compliant substrates. Science 322, 1687–1691 (2008).

    CAS  PubMed  Google Scholar 

  223. Bangasser, B. L., Rosenfeld, S. S. & Odde, D. J. Determinants of maximal force transmission in a motor-clutch model of cell traction in a compliant microenvironment. Biophys. J. 105, 581–592 (2013).

    CAS  PubMed  PubMed Central  Google Scholar 

  224. Escribano, J., Sánchez, M. T. & García-Aznar, J. M. A discrete approach for modeling cell–matrix adhesions. Comput. Part. Mech. 1, 117–130 (2014).

    Google Scholar 

  225. Sabass, B. & Schwarz, U. S. Modeling cytoskeletal flow over adhesion sites: competition between stochastic bond dynamics and intracellular relaxation. J. Phys. Condens. Matter 22, 194112 (2010).

    PubMed  Google Scholar 

  226. Bangasser, B. L. & Odde, D. J. Master equation-based analysis of a motor-clutch model for cell traction force. Cell. Mol. Bioeng. 6, 449–459 (2013).

    PubMed  PubMed Central  Google Scholar 

  227. Sens, P. Rigidity sensing by stochastic sliding friction. EPL 104, 38003 (2013).

    Google Scholar 

  228. Srinivasan, M. & Walcott, S. Binding site models of friction due to the formation and rupture of bonds: state-function formalism, force-velocity relations, response to slip velocity transients, and slip stability. Phys. Rev. E 80, 046124 (2009).

    Google Scholar 

  229. Ley, K., Rivera-Nieves, J., Sandborn, W. J. & Shattil, S. Integrin-based therapeutics: biological basis, clinical use and new drugs. Nat. Rev. Drug Discov. 15, 173–183 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank H. Hamidi for critical reading of the manuscript and text editing. This work was supported by the Spanish Ministry of Economy and Competitiveness (BFU2016-79916-P), the European Commission (H2020-FETPROACT-01-2016-731957), the Generalitat de Catalunya (2017-SGR-1602), Obra Social ‘La Caixa’ and the ICREA Academia programme of ICREA (to P.R.-C.), and ERC Consolidator grant 615258 and an Academy of Finland grant (to J.I.). The Institute for Bioengineering of Catalonia is the recipient of a Severo Ochoa Award of Excellence from the MICINN.

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Nature Reviews Molecular Cell Biology thanks C. Ballestrem and V. Weaver for their contribution to the peer review of this work.

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The authors contributed equally to this work.

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Correspondence to Johanna Ivaska or Pere Roca-Cusachs.

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Glossary

Type I transmembrane proteins

Proteins that span the cell membrane through a single transmembrane α-helix, with the N terminus on the extracellular side of the membrane.

RGD motif

A peptide sequence consisting of arginine, glycine and aspartate. It is found in extracellular matrix molecules such as fibronectin and vitronectin and it serves as a binding site for integrins.

Tetraspanins

Membrane-spanning proteins involved in the formation of specific membrane microdomains that have a role in numerous cellular processes, including cell adhesion, signalling and membrane trafficking. They have four transmembrane α-helices and two extracellular loops with a conserved Cys-Cys-Gly amino acid motif, as well as two other conserved cysteine residues.

Adaptor protein

In the context of integrin adhesions, an adaptor protein is any of the several different types of recruited protein that directly or indirectly link integrins to actin.

Talin

A high molecular weight protein (~270 kDa) that links the integrin β-subunit to actin filaments and promotes the assembly of focal adhesions. It consists of an amino-terminal head region with the F0 and FERM domains, a flexible rod domain and a carboxy-terminal dimerization sequence.

Nascent adhesions

Clusters of activated integrin molecules with sizes smaller than 1 µm. They either undergo fast disassembly or they progress to mature focal adhesions.

Focal adhesions

Nascent adhesions mature to focal adhesions on tension generated by actomyosin contractility or external forces. This leads to protein recruitment, and a change in shape from dotted to larger, elongated structures.

Kindlin

A family of proteins (kindlins 1, 2 and 3) involved in integrin-mediated cell signalling, acting as linkers between the actin cytoskeleton and integrins.

Focal adhesion kinase

(FAK). A tyrosine kinase that is involved in the activation and growth of focal adhesions and has a key role in motility and cell survival.

Lectins

Proteins that bind to carbohydrates with high specificity. They are involved in cell adhesion, cell–cell interaction and cell recognition.

Elastic strain

On application of force to stretch a material, the strain is the change in length divided by the original length. If it is elastic, it will revert to zero when force stops being applied.

Glycocalyx

A meshwork surrounding the cell membrane of many eukaryotic cells and bacteria. It consists of carbohydrates (mostly proteoglycans and glycoproteins) that extend out of the cell membrane.

Fluid-phase endocytosis

Continuous and non-specific uptake of extracellular fluid. This form of endocytosis is not mediated by a specific receptor.

BAR protein

A protein with a BAR (BIN/amphiphysin/RVS) domain. The special banana-shaped conformation of BAR domain dimers creates a pocket of positive charges that could mediate phospholipid binding and curvature sensing or induction.

Cell traction forces

Forces that the contractile action of the actomyosin cytoskeleton in cells exert on a substrate measured per unit area.

Caveolae

Small (~50–100 nm) invaginations of the plasma membrane rich in cholesterol. They are shaped by different proteins, of which the caveolin protein family are the principal components.

Lipid rafts

Subdomains of the plasma membrane rich in cholesterol and glycosphingolipids that are resistant to solubilization by non-ionic detergents. They are thought to serve as protein and signalling hubs.

Fibrillar adhesions

Cell–extracellular matrix adhesion sites rich in α5β1 integrin and tensin. They are located towards the cell centre and usually form along extracellular matrix fibrils.

Stress fibres

Actin bundles rich in non-muscle myosin II and α-actinin. They have an important role in force transmission and cellular contractility in non-muscle cells.

MRTFA

A transcription coactivator whose nuclear translocation is regulated by the balance between F-actin and G-actin in the cell cytoplasm. When not bound to G-actin, it translocates to the nucleus, where it regulates gene expression on association with serum response factor.

YAP/TAZ

Yes-associated protein (YAP) and transcriptional co-activator with PDZ-binding motif (TAZ) are the two mammalian orthologues of Drosophila melanogaster Yorkie. Both proteins are regulated by mechanical signals and the Hippo pathway. In response to mechanical stimulation of the cells or on inhibition of the Hippo pathway, YAP and TAZ translocate to the nucleus, where they can regulate gene expression through their binding to transcription factors of the TEAD family.

Linker of nucleoskeleton and cytoskeleton (LINC) complex

A protein complex that links the inner nuclear lamina with the cytoskeleton. It has important roles in cell migration, nuclear mechanosensing and nuclear positioning.

Basement membrane

A sheet-like extracellular matrix structure rich in laminin, collagen IV and nidogen. It acts as a barrier between parenchymal cells and connective tissue.

Neural crest cells

A multipotent group of cells arising at the border between the neural plate and non-neural ectoderm. After gastrulation, they become specified and undergo a process of epithelial–mesenchymal transition during neurulation, migrating to form distinct cell populations in different tissues.

Carcinomas

Cancers that originate in epithelial tissues such as the skin or in tissues that line or cover internal organs. There are different types of carcinoma, including squamous and basal cell carcinomas, adenocarcinomas, melanomas, papillomas and ductal carcinomas.

Convergent extension

A process of collective cell movement during embryonic development by which tissues undergo elongation over one axis and narrowing over the other axis.

Interstitial

Internal to a tissue but not specific to a particular structure.

Mesenteric basement membrane

A set of connective tissues that attaches the intestine to the abdominal wall. It contains blood vessels, nerves, lymph nodes and fat.

Urokinase plasminogen activator receptor

(uPAR). A glycosylphosphatidylinositol-anchored cell membrane receptor that acts as a receptor for urokinase plasminogen activator. The binding of urokinase plasminogen activator to its receptor is instrumental for the activation of plasminogen to plasmin — an important blood protease implicated in blood clot resolution, which has also been shown to degrade extracellular matrix and has been linked to cancer progression.

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Kechagia, J.Z., Ivaska, J. & Roca-Cusachs, P. Integrins as biomechanical sensors of the microenvironment. Nat Rev Mol Cell Biol 20, 457–473 (2019). https://doi.org/10.1038/s41580-019-0134-2

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