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The role and regulation of integrins in cell migration and invasion

Nature Reviews Molecular Cell Biology volume 26, pages 147–167 (2025)Cite this article

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Abstract

Integrin receptors are the main molecular link between cells and the extracellular matrix (ECM) as well as mediating cell–cell interactions. Integrin–ECM binding triggers the formation of heterogeneous multi-protein assemblies termed integrin adhesion complexes (IACs) that enable integrins to transform extracellular cues into intracellular signals that affect many cellular processes, especially cell motility. Cell migration is essential for diverse physiological and pathological processes and is dysregulated in cancer to favour cell invasion and metastasis. Here, we discuss recent findings on the role of integrins in cell migration with a focus on cancer cell dissemination. We review how integrins regulate the spatial distribution and dynamics of different IACs, covering classical focal adhesions, emerging adhesion types and adhesion regulation. We discuss the diverse roles integrins have during cancer progression from cell migration across varied ECM landscapes to breaching barriers such as the basement membrane, and eventual colonization of distant organs.

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Fig. 1: Integrin heterodimer structure and activation and formation of integrin adhesion complexes.
Fig. 2: Integrin adhesion complexes in cell migration in two and three dimensions.
Fig. 3: Integrin function in acquiring an invasive phenotype.
Fig. 4: Integrins in metastasis.

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References

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

    Article  CAS  PubMed  Google Scholar 

  2. Hynes, R. O. Integrins. Cell 110, 673–687 (2002).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  Google Scholar 

  4. Stanislovas, J. & Kermorgant, S. c-Met-integrin cooperation: mechanisms, tumorigenic effects, and therapeutic relevance. Front. Cell Dev. Biol. 10, 994528 (2022).

    Article  PubMed  PubMed Central  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  6. Yamada, K. M. & Sixt, M. Mechanisms of 3D cell migration. Nat. Rev. Mol. Cell Biol. 20, 738–752 (2019).

    Article  CAS  PubMed  Google Scholar 

  7. SenGupta, S., Parent, C. A. & Bear, J. E. The principles of directed cell migration. Nat. Rev. Mol. Cell Biol. 22, 529–547 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  8. Green, H. J. & Brown, N. H. Integrin intracellular machinery in action. Exp. Cell Res. 378, 226–231 (2019).

    Article  CAS  PubMed  Google Scholar 

  9. Orré, T., Rossier, O. & Giannone, G. The inner life of integrin adhesion sites: from single molecules to functional macromolecular complexes. Exp. Cell Res. 379, 235–244 (2019).

    Article  PubMed  Google Scholar 

  10. Saraswathibhatla, A., Indana, D. & Chaudhuri, O. Cell–extracellular matrix mechanotransduction in 3D HHS Public Access. Nat. Rev. Mol. Cell Biol. 24, 495–516 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Kanchanawong, P. & Calderwood, D. A. Organization, dynamics and mechanoregulation of integrin-mediated cell–ECM adhesions. Nat. Rev. Mol. Cell Biol. 24, 142–161 (2023).

    Article  CAS  PubMed  Google Scholar 

  12. Kechagia, J. Z., Ivaska, J. & Roca-Cusachs, P. Integrins as biomechanical sensors of the microenvironment. Nat. Rev. Mol. Cell Biol. 20, 457–473 (2019).

    Article  CAS  PubMed  Google Scholar 

  13. Luo, B.-H., Carman, C. V. & Springer, T. A. Structural basis of integrin regulation and signaling. Annu. Rev. Immunol. 25, 619–647 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  14. Anderson, J. M., Li, J. & Springer, T. A. Regulation of integrin α5β1 conformational states and intrinsic affinities by metal ions and the ADMIDAS. Mol. Biol. Cell 33, ar56 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Zhang, K. & Chen, J. The regulation of integrin function by divalent cations. Cell Adh. Migr. 6, 20–29 (2012).

    Article  PubMed  PubMed Central  Google Scholar 

  16. 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).

    Article  CAS  PubMed  Google Scholar 

  17. Campbell, I. D. & Humphries, M. J. Integrin structure, activation, and interactions. Cold Spring Harb. Perspect. Biol. 3, a004994 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  18. Kolasangiani, R., Bidone, T. C. & Schwartz, M. A. Integrin conformational dynamics and mechanotransduction. Cells 11, 3584 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Vinogradova, O. et al. A structural mechanism of integrin αIIbβ3 “inside-out” activation as regulated by its cytoplasmic face. Cell 110, 587–597 (2002). This study provides a structural mechanism by which a handshake between the α-subunit and the β-subunit cytoplasmic integrin tails restrains the integrin in a resting state and finds that unclasping of this interaction triggers the inside-out conformational signal that leads to receptor activation.

    Article  CAS  PubMed  Google Scholar 

  20. Shafaq-Zadah, M. et al. Spatial N-glycan rearrangement on α5β1 integrin nucleates galectin-3 oligomers to determine endocytic fate. Preprint at bioRxiv https://doi.org/10.1101/2023.10.27.564026 (2023).

  21. Cormier, A. et al. Cryo-EM structure of the αvβ8 integrin reveals a mechanism for stabilizing integrin extension. Nat. Struct. Mol. Biol. 25, 698–704 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Schumacher, S. et al. Structural insights into integrin α5β1 opening by fibronectin ligand. Sci. Adv. 7, eabe9716 (2021). This study reports cryo electron microscopy structures of human α5β1 integrin in its extended fibronectin-bound state and in its resting state in a half-bent conformation, and shows that affinity of α5β1 integrin for fibronectin is increased with manganese ions (Mn2+) while adopting the half-bent conformation, indicating that ligand-binding affinity is independent of conformation, and showing that α5β1 integrin opening is induced by ligand-binding.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  23. Li, J. et al. Ligand binding initiates single-molecule integrin conformational activation. Cell 187, 2990–3005.e17 (2024). This study uses fluorescence resonance energy transfer to investigate conformational regulation of α5β1 integrin, finding that ligand binding to bent integrin triggers rapid receptor extension and activation.

    Article  CAS  PubMed  Google Scholar 

  24. Askari, J. A. et al. Focal adhesions are sites of integrin extension. J. Cell Biol. 188, 891–903 (2010). This study uses fluorescence resonance energy transfer to demonstrate that integrin α5β1 is found in the extended conformation inside IACs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Adair, B. D., Xiong, J.-P., Yeager, M. & Arnaout, M. A. Cryo-EM structures of full-length integrin αIIbβ3 in native lipids. Nat. Commun. 14, 4168 (2023). This work reports cryo electron microscopy structures of full-length αIIbβ3 integrin in its apo state in native cell membrane-based nanoparticles, showing that this integrin adopts the bent inactive state but with a fully accessible ligand-binding site. This finding challenges the model that this site is occluded by the plasma membrane.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Calderwood, D. A. et al. The talin head domain binds to integrin β subunit cytoplasmic tails and regulates integrin activation. J. Biol. Chem. 274, 28071–28074 (1999).

    Article  CAS  PubMed  Google Scholar 

  27. Haydari, Z., Shams, H., Jahed, Z. & Mofrad, M. R. K. Kindlin assists talin to promote integrin activation. Biophys. J. 118, 1977–1991 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  28. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  29. Grzesiak, J. J. & Pierschbacher, M. D. Shifts in the concentrations of magnesium and calcium in early porcine and rat wound fluids activate the cell migratory response. J. Clin. Invest. 95, 227–233 (1995).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  30. Kong, F., García, 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). Using atomic force microscopy, this study observes triphasic force-dependent bond lifetimes that deviate from the Bell model, demonstrating fibronectin–α5β1 integrin catch bonds which provide a physical mechanism for integrin-mediated force sensing.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  31. 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).

    Article  PubMed  Google Scholar 

  32. Kiema, T. et al. The molecular basis of filamin binding to integrins and competition with talin. Mol. Cell 21, 337–347 (2006).

    Article  CAS  PubMed  Google Scholar 

  33. Bouvard, D. et al. Disruption of focal adhesions by integrin cytoplasmic domain-associated protein-1α. J. Biol. Chem. 278, 6567–6574 (2003).

    Article  CAS  PubMed  Google Scholar 

  34. Rantala, J. K. et al. SHARPIN is an endogenous inhibitor of β1-integrin activation. Nat. Cell Biol. 13, 1315–1324 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  35. Pouwels, J. et al. SHARPIN regulates uropod detachment in migrating lymphocytes. Cell Rep. 5, 619–628 (2013).

    Article  CAS  PubMed  Google Scholar 

  36. Kasirer-Friede, A., Peuhu, E., Ivaska, J. & Shattil, S. J. Platelet SHARPIN regulates platelet adhesion and inflammatory responses through associations with αIIbβ3 and LUBAC. Blood Adv. 6, 2595–2607 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Siitonen, R. et al. 68Ga-DOTA-E[C(RGDFK)]2 PET imaging of sharpin-regulated integrin activity in mice. J. Nucl. Med. 60, 1380–1387 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  38. Gao, J. et al. Sharpin suppresses β1-integrin activation by complexing with the β1 tail and kindlin-1. Cell Commun. Signal. 17, 101 (2019).

    Article  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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Zaidel-Bar, R., Itzkovitz, S., Ma’ayan, A., Iyengar, R. & Geiger, B. Functional atlas of the integrin adhesome. Nat. Cell Biol. 9, 858–867 (2007). This work presents a detailed description of the ‘integrin adhesome’, consisting of a complex network of 156 components linked together and modified by 690 interactions, revealing several functional ‘subnets’ that are involved in regulation of cell adhesion, migration and cytoskeletal organization.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Chastney, M. R., Conway, J. R. W. & Ivaska, J. Integrin adhesion complexes. Curr. Biol. 31, R536–R542 (2021).

    Article  CAS  PubMed  Google Scholar 

  42. Conway, J. R. W. & Jacquemet, G. Cell matrix adhesion in cell migration. Essays Biochem. 63, 535–551 (2019).

    Article  CAS  PubMed  Google Scholar 

  43. Michael, M. & Parsons, M. New perspectives on integrin-dependent adhesions. Curr. Opin. Cell Biol. 63, 31–37 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. 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).

    Article  CAS  PubMed  Google Scholar 

  46. Hanein, D. & Horwitz, A. R. The structure of cell–matrix adhesions: the new frontier. Curr. Opin. Cell Biol. 24, 134–140 (2012).

    Article  CAS  PubMed  Google Scholar 

  47. Zaidel-Bar, R., Ballestrem, C., Kam, Z. & Geiger, B. Early molecular events in the assembly of matrix adhesions at the leading edge of migrating cells. J. Cell Sci. 116, 4605–4613 (2003).

    Article  CAS  PubMed  Google Scholar 

  48. Bachir, A. I. et al. Integrin-associated complexes form hierarchically with variable stoichiometry in nascent adhesions. Curr. Biol. 24, 1845–1853 (2014). This work presents a hierarchical description of integrin-containing molecular complexes and their stoichiometry in nascent adhesions at high spatial and temporal resolution, establishing a model whereby transient α-actinin–integrin complexes help nucleate nascent adhesions within the lamellipodium.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  49. Han, S. J. et al. Pre-complexation of talin and vinculin without tension is required for efficient nascent adhesion maturation. eLife 10, e66151 (2021). This article demonstrates that IAC components can preassemble in the cytoplasm and are incorporated into newly forming adhesions as ‘units’.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  50. Zaidel-Bar, R., Cohen, M., Addadi, L. & Geiger, B. Hierarchical assembly of cell–matrix adhesion complexes. Biochem. Soc. Trans. 32, 416–420 (2004).

    Article  CAS  PubMed  Google Scholar 

  51. Han, S. J., Oak, Y., Groisman, A. & Danuser, G. Traction microscopy to identify force modulation in subresolution adhesions. Nat. Methods 12, 653–656 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  53. Mathieu, M., Isomursu, A. & Ivaska, J. Positive and negative durotaxis—mechanisms and emerging concepts. J. Cell Sci. 137, jcs261919 (2024).

    Article  CAS  PubMed  Google Scholar 

  54. Atherton, P. et al. Tensin3 interaction with talin drives the formation of fibronectin-associated fibrillar adhesions. J. Cell Biol. 221, e202107022 (2022). This work demonstrates tensin 3 interaction with talin and the requirement of this talin–tensin 3 interaction in fibrillar adhesions and fibronectin fibrillogenesis.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  55. Barber-Pérez, N. et al. Mechano-responsiveness of fibrillar adhesions on stiffness-gradient gels. J. Cell Sci. 133, jcs242909 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  56. Clark, K. et al. A specific α5β1-integrin conformation promotes directional integrin translocation and fibronectin matrix formation. J. Cell Sci. 118, 291–300 (2005).

    Article  CAS  PubMed  Google Scholar 

  57. Pankov, R. et al. Integrin dynamics and matrix assembly: tensin-dependent translocation of α5β1 integrins promotes early fibronectin fibrillogenesis. J. Cell Biol. 148, 1075–1090 (2000).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  58. Zamir, E. et al. Dynamics and segregation of cell–matrix adhesions in cultured fibroblasts. Nat. Cell Biol. 2, 191–196 (2000).

    Article  CAS  PubMed  Google Scholar 

  59. Case, L. B., De Pasquale, M., Henry, L. & Rosen, M. K. Synergistic phase separation of two pathways promotes integrin clustering and nascent adhesion formation. eLife 11, e72588 (2022). This study finds that two IAC components, p130Cas and FAK, undergo LLPS in vitro and in cells, and that mutations inhibiting or enhancing phase separation in vitro respectively reduce or increase the number of IACs.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  60. Cheng, X. & Case, L. B. Phase separation in chemical and mechanical signal transduction. Curr. Opin. Cell Biol. 85, 102243 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  61. Guo, K. et al. KANK1 shapes focal adhesions by orchestrating protein binding, mechanical force sensing, and phase separation. Cell Rep. 42, 113321 (2023).

    Article  CAS  PubMed  Google Scholar 

  62. Lee, Y.-R. J., Yamada, S. & Lo, S. H. Phase transition of tensin-1 during the focal adhesion disassembly and cell division. Proc. Natl Acad. Sci. USA 120, e2303037120 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  63. Wang, Y. et al. LIMD1 phase separation contributes to cellular mechanics and durotaxis by regulating focal adhesion dynamics in response to force. Dev. Cell 56, 1313–1325.e7 (2021).

    Article  CAS  PubMed  Google Scholar 

  64. Byron, A. et al. Characterisation of a nucleo-adhesome. Nat. Commun. 13, 3053 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  66. Miao, M. Z. et al. Redox-active endosomes mediate α5β1 integrin signaling and promote chondrocyte matrix metalloproteinase production in osteoarthritis. Sci. Signal. 16, eadf8299 (2023). Together with Alanko et al. (2015), this study demonstrates active integrin signalling from endosomes, following integrin ligand stimulation and endocytosis, regulating either anchorage-independent cell survival or ROS signalling and matrix degradation.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  67. Jacquemet, G. et al. Filopodome mapping identifies p130Cas as a mechanosensitive regulator of filopodia stability. Curr. Biol. 29, 202–216.e7 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  68. Lock, J. G. et al. Clathrin-containing adhesion complexes. J. Cell Biol. 218, 2086–2095 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  69. Walko, G., Castañón, M. J. & Wiche, G. Molecular architecture and function of the hemidesmosome. Cell Tissue Res. 360, 363–378 (2015).

    Article  CAS  PubMed  Google Scholar 

  70. te Molder, L., de Pereda, J. M. & Sonnenberg, A. Regulation of hemidesmosome dynamics and cell signaling by integrin α6β4. J. Cell Sci. 134, jcs259004 (2021).

  71. Lock, J. G. et al. Reticular adhesions are a distinct class of cell-matrix adhesions that mediate attachment during mitosis. Nat. Cell Biol. 20, 1290–1302 (2018). This seminal Review summarizes the new type of IAC-mediated adhesions and their potential implications for the field.

    Article  CAS  PubMed  Google Scholar 

  72. Hakanpää, L. et al. Reticular adhesions are assembled at flat clathrin lattices and opposed by active integrin α5β1. J. Cell Biol. 222, e202303107 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  73. Zuidema, A., Wang, W. & Sonnenberg, A. Crosstalk between cell adhesion complexes in regulation of mechanotransduction. BioEssays 42, e2000119 (2020).

    Article  PubMed  Google Scholar 

  74. Elkhatib, N. et al. Tubular clathrin/AP-2 lattices pinch collagen fibers to support 3D cell migration. Science 356, eaal4713 (2017).

    Article  PubMed  Google Scholar 

  75. Zhang, W. et al. Curved adhesions mediate cell attachment to soft matrix fibres in three dimensions. Nat. Cell Biol. 25, 1453–1464 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  76. Fujiwara, T. K. et al. Ultrafast single-molecule imaging reveals focal adhesion nano-architecture and molecular dynamics. J. Cell Biol. 222, e202110162 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  77. Spiess, M. et al. Active and inactive β1 integrins segregate into distinct nanoclusters in focal adhesions. J. Cell Biol. 217, 1929–1940 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  78. Hu, S. et al. Structured illumination microscopy reveals focal adhesions are composed of linear subunits. Cytoskeleton 72, 235–245 (2015).

    Article  PubMed  Google Scholar 

  79. Cheng, B. et al. Nanoscale integrin cluster dynamics controls cellular mechanosensing via FAKY397 phosphorylation. Sci. Adv. 6, eaax1909 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  80. Changede, R., Cai, H., Wind, S. J. & Sheetz, M. P. Integrin nanoclusters can bridge thin matrix fibres to form cell–matrix adhesions. Nat. Mater. 18, 1366–1375 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  81. Di Russo, J. et al. Integrin α5β1 nano-presentation regulates collective keratinocyte migration independent of substrate rigidity. eLife 10, e69861 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  82. Hennig, K. et al. Stick-slip dynamics of cell adhesion triggers spontaneous symmetry breaking and directional migration of mesenchymal cells on one-dimensional lines. Sci. Adv. 6, eaau5670 (2020). This study fabricates thin 1D ECM lines, mimicking in vivo tissue ECM fibres, and describes experimentally and theoretically how a generic stick–slip behaviour initiated by contractility-dependent stochastic detachment of adhesive contacts at one side of the cell is sufficient to trigger cell motility in one dimension in the absence of pre-established polarity.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  83. Le Saux, G. et al. Spacing of integrin ligands influences signal transduction in endothelial cells. Biophys. J. 101, 764–773 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  84. Oria, R. et al. Force loading explains spatial sensing of ligands by cells. Nature 552, 219–224 (2017). This study challenges the notion of a ‘molecular ruler’ in dictating cell adhesion responses to differentially spaced ECM ligands and provides, using the molecular-clutch model, a general framework for how cells sense spatial and physical information at the nanoscale.

    Article  CAS  PubMed  Google Scholar 

  85. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  86. Hawkes, W. et al. Regulation of cardiomyocyte adhesion and mechanosignalling through distinct nanoscale behaviour of integrin ligands mimicking healthy or fibrotic extracellular matrix. Philos. Trans. R. Soc. B 377, 20220021 (2022).

    Article  CAS  Google Scholar 

  87. Levario-Diaz, V. et al. 1D micro-nanopatterned integrin ligand surfaces for directed cell movement. Front. Cell Dev. Biol. 10, 972624 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  88. Young, J. L., Holle, A. W. & Spatz, J. P. Nanoscale and mechanical properties of the physiological cell–ECM microenvironment. Exp. Cell Res. 343, 3–6 (2016).

    Article  CAS  PubMed  Google Scholar 

  89. Wallace, J. M. et al. Type I collagen exists as a distribution of nanoscale morphologies in teeth, bones, and tendons. Langmuir 26, 7349–7354 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  90. Früh, S. M., Schoen, I., Ries, J. & Vogel, V. Molecular architecture of native fibronectin fibrils. Nat. Commun. 6, 7275 (2015).

    Article  PubMed  Google Scholar 

  91. Reuten, R., Mayorca-Guiliani, A. E. & Erler, J. T. Matritecture: mapping the extracellular matrix architecture during health and disease. Matrix Biol. 14, 100102 (2022).

    Article  CAS  Google Scholar 

  92. Pally, D. & Naba, A. Extracellular matrix dynamics: a key regulator of cell migration across length-scales and systems. Curr. Opin. Cell Biol. 86, 102309 (2024).

    Article  CAS  PubMed  Google Scholar 

  93. Dibus, M., Joshi, O. & Ivaska, J. Novel tools to study cell–ECM interactions, cell adhesion dynamics and migration. Curr. Opin. Cell Biol. 88, 102355 (2024).

    Article  PubMed  Google Scholar 

  94. Conway, J. R. W. et al. Defined extracellular matrix compositions support stiffness-insensitive cell spreading and adhesion signaling. Proc. Natl Acad. Sci. USA 120, e2304288120 (2023). This study analyses cell spreading on arrays of different ECM components printed on soft and stiff hydrogels to demonstrate that availability of ECM ligands and the integrins they engage jointly determines cell behaviour in response to matrix rigidity and can trigger ‘stiff-like’ cell spreading on soft substrate.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  95. Isomursu, A. et al. Dynamic micropatterning reveals substrate‐dependent differences in the geometric control of cell polarization and migration. Small Methods 8, e2300719 (2024).

    Article  PubMed  Google Scholar 

  96. Franco, S. J. et al. Calpain-mediated proteolysis of talin regulates adhesion dynamics. Nat. Cell Biol. 6, 977–983 (2004).

    Article  CAS  PubMed  Google Scholar 

  97. Moreno-Layseca, P. et al. Cargo-specific recruitment in clathrin- and dynamin-independent endocytosis. Nat. Cell Biol. 23, 1073–1084 (2021).

    Article  CAS  PubMed Central  Google Scholar 

  98. Zaidel-Bar, R., Milo, R., Kam, Z. & Geiger, B. A paxillin tyrosine phosphorylation switch regulates the assembly and form of cell–matrix adhesions. J. Cell Sci. 120, 137–148 (2007).

    Article  CAS  PubMed  Google Scholar 

  99. Wilhelmsen, K. et al. Serine phosphorylation of the integrin β4 subunit is necessary for epidermal growth factor receptor-induced hemidesmosome disruption. Mol. Biol. Cell 18, 3512–3522 (2007).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  100. Ezratty, E. J., Partridge, M. A. & Gundersen, G. G. Microtubule-induced focal adhesion disassembly is mediated by dynamin and focal adhesion kinase. Nat. Cell Biol. 7, 581–590 (2005).

    Article  CAS  PubMed  Google Scholar 

  101. Seetharaman, S. & Etienne-Manneville, S. Microtubules at focal adhesions—a double-edged sword. J. Cell Sci. 132, jcs232843 (2019).

    Article  CAS  PubMed  Google Scholar 

  102. Yao, M. et al. Force- and cell state-dependent recruitment of Piezo1 drives focal adhesion dynamics and calcium entry. Sci. Adv. 8, eabo1461 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  103. Chan, K. T., Bennin, D. A. & Huttenlocher, A. Regulation of adhesion dynamics by calpain-mediated proteolysis of focal adhesion kinase (FAK). J. Biol. Chem. 285, 11418–11426 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  104. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  105. Yue, J. et al. Microtubules regulate focal adhesion dynamics through MAP4K4. Dev. Cell 31, 572–585 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  106. Kenific, C. M. et al. NBR1 enables autophagy-dependent focal adhesion turnover. J. Cell Biol. 212, 577–590 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  107. Sharifi, M. N. et al. Autophagy promotes focal adhesion disassembly and cell motility of metastatic tumor cells through the direct interaction of paxillin with LC3. Cell Rep. 15, 1660–1672 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  108. Juanes, M. A. et al. The role of APC-mediated actin assembly in microtubule capture and focal adhesion turnover. J. Cell Biol. 218, 3415–3435 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  109. Zhao, Y., Wang, Y., Sarkar, A. & Wang, X. Keratocytes generate high integrin tension at the trailing edge to mediate rear de-adhesion during rapid cell migration. iScience 9, 502–512 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  110. llić, D. et al. Reduced cell motility and enhanced focal adhesion contact formation in cells from FAK-deficient mice. Nature 377, 539–544 (1995).

    Article  Google Scholar 

  111. Webb, D. J. et al. FAK–Src signalling through paxillin, ERK and MLCK regulates adhesion disassembly. Nat. Cell Biol. 6, 154–161 (2004).

    Article  CAS  PubMed  Google Scholar 

  112. Li, X., Combs, J. D., Salaita, K. & Shu, X. Polarized focal adhesion kinase activity within a focal adhesion during cell migration. Nat. Chem. Biol. 19, 1458–1468 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  113. Jones, M. C., Askari, J. A., Humphries, J. D. & Humphries, M. J. Cell adhesion is regulated by CDK1 during the cell cycle. J. Cell Biol. 217, 3203–3218 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  114. Gough, R. E. et al. Talin mechanosensitivity is modulated by a direct interaction with cyclin-dependent kinase-1. J. Biol. Chem. 297, 100837 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  115. Kaverina, I., Krylyshkina, O. & Small, J. V. Microtubule targeting of substrate contacts promotes their relaxation and dissociation. J. Cell Biol. 146, 1033–1044 (1999).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  116. Stehbens, S. J. et al. CLASPs link focal-adhesion-associated microtubule capture to localized exocytosis and adhesion site turnover. Nat. Cell Biol. 16, 558–570 (2014).

    Article  Google Scholar 

  117. Tadijan, A., Samaržija, I., Humphries, J. D., Humphries, M. J. & Ambriović-Ristov, A. KANK family proteins in cancer. Int. J. Biochem. Cell Biol. 131, 105903 (2021).

    Article  CAS  PubMed  Google Scholar 

  118. Bouchet, B. P. et al. Talin–KANK1 interaction controls the recruitment of cortical microtubule stabilizing complexes to focal adhesions. eLife 5, e18124 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  119. Sun, Z. et al. Kank2 activates talin, reduces force transduction across integrins and induces central adhesion formation. Nat. Cell Biol. 18, 941–953 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  120. Li, X., Goult, B. T., Ballestrem, C. & Zacharchenko, T. The structural basis of the talin–KANK1 interaction that coordinates the actin and microtubule cytoskeletons at focal adhesions. Open. Biol. 13, 230058 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  121. Théry, M., Pépin, A., Dressaire, E., Chen, Y. & Bornens, M. Cell distribution of stress fibres in response to the geometry of the adhesive environment. Cell Motil. Cytoskeleton 63, 341–355 (2006).

    Article  PubMed  Google Scholar 

  122. Lee, G., Han, S.-B. & Kim, D.-H. Cell–ECM contact-guided intracellular polarization is mediated via lamin A/C dependent nucleus-cytoskeletal connection. Biomaterials 268, 120548 (2021).

    Article  CAS  PubMed  Google Scholar 

  123. Autenrieth, T. J. et al. Actomyosin contractility and RhoGTPases affect cell-polarity and directional migration during haptotaxis. Integr. Biol. 8, 1067–1078 (2016).

    Article  CAS  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  125. Isomursu, A. et al. Directed cell migration towards softer environments. Nat. Mater. 21, 1081–1090 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  126. Park, J., Kim, D.-H. & Levchenko, A. Topotaxis: a new mechanism of directed cell migration in topographic ECM gradients. Biophys. J. 114, 1257–1263 (2018).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  127. Fischer, R. S. et al. Contractility, focal adhesion orientation, and stress fiber orientation drive cancer cell polarity and migration along wavy ECM substrates. Proc. Natl Acad. Sci. USA 118, e2021135118 (2021). This study designs nanotopographic ECM-coated substrates that mimic collagen fibril waveforms seen in tumours and healthy tissues, and demonstrates that wave amplitude and cell contractility determine how cancer cells polarize and migrate. The study proposes that sufficiently high-amplitude ECM waves around tumours may serve as ‘cell polarization barriers’, decreasing directional migration of tumour cells.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  128. Zimmerman, S. P., Asokan, S. B., Kuhlman, B. & Bear, J. E. Cells lay their own tracks—optogenetic Cdc42 activation stimulates fibronectin deposition supporting directed migration. J. Cell Sci. 130, 2971–2983 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  129. Sarkar, A., LeVine, D. N., Kuzmina, N., Zhao, Y. & Wang, X. Cell migration driven by self-generated integrin ligand gradient on ligand-labile surfaces. Curr. Biol. 30, 4022–4032.e5 (2020). This work reports a unique mode of cell migration whereby the cells generate a gradient of ligand surface density underneath the cell body by constantly rupturing labile integrin ligands in a manner that drives and guides cell migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  130. Clark, A. G. et al. Self-generated gradients steer collective migration on viscoelastic collagen networks. Nat. Mater. 21, 1200–1210 (2022).

    Article  CAS  PubMed  Google Scholar 

  131. Winkler, J., Abisoye-Ogunniyan, A., Metcalf, K. J. & Werb, Z. Concepts of extracellular matrix remodelling in tumour progression and metastasis. Nat. Commun. 11, 5120 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  132. Hebert, J. D. et al. Proteomic profiling of the ECM of xenograft breast cancer metastases in different organs reveals distinct metastatic niches. Cancer Res. 80, 1475–1485 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  133. Papanicolaou, M. et al. Temporal profiling of the breast tumour microenvironment reveals collagen XII as a driver of metastasis. Nat. Commun. 13, 4587 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  134. Su, C. et al. The biological functions and clinical applications of integrins in cancers. Front. Pharmacol. 11, 579068 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  135. Cooper, J. & Giancotti, F. G. Integrin signaling in cancer: mechanotransduction, stemness, epithelial plasticity, and therapeutic resistance. Cancer Cell 35, 347–367 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  136. Dongre, A. & Weinberg, R. A. New insights into the mechanisms of epithelial–mesenchymal transition and implications for cancer. Nat. Rev. Mol. Cell Biol. 20, 69–84 (2019).

    Article  CAS  PubMed  Google Scholar 

  137. Margadant, C. & Sonnenberg, A. Integrin–TGF‐β crosstalk in fibrosis, cancer and wound healing. EMBO Rep. 11, 97–105 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  138. Buckley, C. E. & St Johnston, D. Apical–basal polarity and the control of epithelial form and function. Nat. Rev. Mol. Cell Biol. 23, 559–577 (2022).

    Article  CAS  PubMed  Google Scholar 

  139. Pora, A., Yoon, S., Windoffer, R. & Leube, R. E. Hemidesmosomes and focal adhesions treadmill as separate but linked entities during keratinocyte migration. J. Invest. Dermatol. 139, 1876–1888.e4 (2019).

    Article  CAS  PubMed  Google Scholar 

  140. Colburn, Z. T. & Jones, J. C. R. α6β4 integrin regulates the collective migration of epithelial cells. Am. J. Respir. Cell Mol. Biol. 56, 443–452 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  141. Nisticò, P., Di Modugno, F., Spada, S. & Bissell, M. J. β1 and β4 integrins: from breast development to clinical practice. Breast Cancer Res. 16, 459 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  142. Knox, J. D. et al. Differential expression of extracellular matrix molecules and the α6-integrins in the normal and neoplastic prostate. Am. J. Pathol. 145, 167–174 (1994).

    CAS  PubMed  PubMed Central  Google Scholar 

  143. Wenta, T. et al. Disassembly of α6β4-mediated hemidesmosomal adhesions promotes tumorigenesis in PTEN-negative prostate cancer by targeting plectin to focal adhesions. Oncogene 41, 3804–3820 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  144. Schmidt, A., Kaakinen, M., Wenta, T. & Manninen, A. Loss of α6β4 integrin-mediated hemidesmosomes promotes prostate epithelial cell migration by stimulating focal adhesion dynamics. Front. Cell Dev. Biol. 10, 886569 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  145. Canel, M., Serrels, A., Frame, M. C. & Brunton, V. G. E-cadherin–integrin crosstalk in cancer invasion and metastasis. J. Cell Sci. 126, 393–401 (2013).

    Article  CAS  PubMed  Google Scholar 

  146. Bejar-Padilla, V. et al. α-Catenin-dependent vinculin recruitment to adherens junctions is antagonistic to focal adhesions. Mol. Biol. Cell 33, 1–9 (2022).

    Article  Google Scholar 

  147. Borghi, N., Lowndes, M., Maruthamuthu, V., Gardel, M. L. & Nelson, W. J. Regulation of cell motile behavior by crosstalk between cadherin- and integrin-mediated adhesions. Proc. Natl Acad. Sci. USA 107, 13324–13329 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  148. Huber, M., Casares-Arias, J., Fässler, R., Müller, D. J. & Strohmeyer, N. In mitosis integrins reduce adhesion to extracellular matrix and strengthen adhesion to adjacent cells. Nat. Commun. 14, 2143 (2023). This study demonstrates a functional role for unengaged β1 integrins in strengthening the cell–cell adhesion of mitotic cells to adjacent cells, supported by vinculin, kindlin and talin 1.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  149. Hadjisavva, R., Anastasiou, O., Ioannou, P. S., Zheltkova, M. & Skourides, P. A. Adherens junctions stimulate and spatially guide integrin activation and extracellular matrix deposition. Cell Rep. 40, 111091 (2022).

    Article  CAS  PubMed  Google Scholar 

  150. Figueiredo, J. et al. Integrin β1 orchestrates the abnormal cell-matrix attachment and invasive behaviour of E-cadherin dysfunctional cells. Gastric Cancer 25, 124–137 (2022).

    Article  CAS  PubMed  Google Scholar 

  151. Roskoski, R. Src kinase regulation by phosphorylation and dephosphorylation. Biochem. Biophys. Res. Commun. 331, 1–14 (2005).

    Article  CAS  PubMed  Google Scholar 

  152. Howden, J. D., Michael, M., Hight-Warburton, W. & Parsons, M. α2β1 integrins spatially restrict Cdc42 activity to stabilise adherens junctions. BMC Biol. 19, 130 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  153. Kilinc, A. N., Han, S., Barrett, L. A., Anandasivam, N. & Nelson, C. M. Integrin-linked kinase tunes cell–cell and cell–matrix adhesions to regulate the switch between apoptosis and EMT downstream of TGFβ1. Mol. Biol. Cell 32, 402–412 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  154. Goodwin, K. et al. Cell–cell and cell–extracellular matrix adhesions cooperate to organize actomyosin networks and maintain force transmission during dorsal closure. Mol. Biol. Cell 28, 1301–1310 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  155. Kim, L. T. & Yamada, K. M. Evidence that β1 integrins in keratinocyte cell–cell junctions are not in the ligand-occupied conformation. J. Invest. Dermatol. 108, 876–880 (1997).

    Article  CAS  PubMed  Google Scholar 

  156. Thölmann, S. et al. JAM-A interacts with α3β1 integrin and tetraspanins CD151 and CD9 to regulate collective cell migration of polarized epithelial cells. Cell. Mol. Life Sci. 79, 88 (2022).

    Article  PubMed  PubMed Central  Google Scholar 

  157. Yang, J. et al. Guidelines and definitions for research on epithelial–mesenchymal transition. Nat. Rev. Mol. Cell Biol. 21, 341–352 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  158. Gandalovičová, A., Vomastek, T., Rosel, D. & Brábek, J. Cell polarity signaling in the plasticity of cancer cell invasiveness. Oncotarget 7, 25022–25049 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  159. Lambert, A. W., Pattabiraman, D. R. & Weinberg, R. A. Emerging biological principles of metastasis. Cell 168, 670–691 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  160. Bornes, L., Belthier, G. & van Rheenen, J. Epithelial-to-mesenchymal transition in the light of plasticity and hybrid E/M states. J. Clin. Med. 10, 2403 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  161. Jolly, M. K. et al. Hybrid epithelial/mesenchymal phenotypes promote metastasis and therapy resistance across carcinomas. Pharmacol. Ther. 194, 161–184 (2019).

    Article  CAS  PubMed  Google Scholar 

  162. Kariya, Y., Oyama, M., Suzuki, T. & Kariya, Y. αvβ3 integrin induces partial EMT independent of TGF-β signaling. Commun. Biol. 4, 490 (2021).

  163. Yamashita, N. et al. Epithelial paradox: clinical significance of coexpression of E-cadherin and vimentin with regard to invasion and metastasis of breast cancer. Clin. Breast Cancer 18, e1003–e1009 (2018).

    Article  CAS  PubMed  Google Scholar 

  164. 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).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  165. Rice, A. J. et al. Matrix stiffness induces epithelial–mesenchymal transition and promotes chemoresistance in pancreatic cancer cells. Oncogenesis 6, e352 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  166. Fattet, L. et al. Matrix rigidity controls epithelial–mesenchymal plasticity and tumor metastasis via a mechanoresponsive EPHA2/LYN complex. Dev. Cell 54, 302–316.e7 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  167. Munger, J. S. & Sheppard, D. Cross talk among TGF-β signaling pathways, integrins, and the extracellular matrix. Cold Spring Harb. Perspect. Biol. 3, a005017 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  168. Machado Brandão-Costa, R. et al. Extracellular matrix derived from high metastatic human breast cancer triggers epithelial–mesenchymal transition in epithelial breast cancer cells through αvβ3 integrin. Int. J. Mol. Sci. 21, 2995 (2020).

    Article  PubMed Central  Google Scholar 

  169. Loh, C.-Y. et al. The E-cadherin and N-cadherin switch in epithelial-to-mesenchymal transition: signaling, therapeutic implications, and challenges. Cells 8, 1118 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  170. Li, X.-L. et al. Integrin β4 promotes cell invasion and epithelial–mesenchymal transition through the modulation of Slug expression in hepatocellular carcinoma. Sci. Rep. 7, 40464 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  171. Cruz, S. P. et al. Dampened regulatory circuitry of TEAD1/ITGA1/ITGA2 promotes TGFβ1 signaling to orchestrate prostate cancer progression. Adv. Sci. 11, e2305547 (2024).

    Article  Google Scholar 

  172. Sasaki, N. et al. TGF-β1 increases cellular invasion of colorectal neuroendocrine carcinoma cell line through partial epithelial–mesenchymal transition. Biochem. Biophys. Rep. 30, 101239 (2022).

    CAS  PubMed  PubMed Central  Google Scholar 

  173. Huang, W., Zhu, J., Shi, H., Wu, Q. & Zhang, C. ITGA2 overexpression promotes esophageal squamous cell carcinoma aggression via FAK/AKT signaling pathway. Onco. Targets Ther. 14, 3583–3596 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  174. Gaballa, R. et al. Exosomes-mediated transfer of Itga2 promotes migration and invasion of prostate cancer cells by inducing epithelial–mesenchymal transition. Cancers 12, 2300 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  175. Salemi, Z., Azizi, R., Fallahian, F. & Aghaei, M. Integrin α2β1 inhibition attenuates prostate cancer cell proliferation by cell cycle arrest, promoting apoptosis and reducing epithelial–mesenchymal transition. J. Cell. Physiol. 236, 4954–4965 (2021).

    Article  CAS  PubMed  Google Scholar 

  176. Kai, F., Drain, A. P. & Weaver, V. M. The extracellular matrix modulates the metastatic journey. Dev. Cell 49, 332–346 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  177. Chang, J. & Chaudhuri, O. Beyond proteases: basement membrane mechanics and cancer invasion. J. Cell Biol. 218, 2456–2469 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  178. Vilchez Mercedes, S. A. et al. Decoding leader cells in collective cancer invasion. Nat. Rev. Cancer 21, 592–604 (2021).

    Article  CAS  PubMed  Google Scholar 

  179. Friedl, P., Locker, J., Sahai, E. & Segall, J. E. Classifying collective cancer cell invasion. Nat. Cell Biol. 14, 777–783 (2012).

    Article  PubMed  Google Scholar 

  180. Baschieri, F. et al. Fibroblasts generate topographical cues that steer cancer cell migration. Sci. Adv. 9, eade2120 (2023). This work reports that migrating fibroblasts deposit a network of tubular structures on their substrate that serves as a guidance cue for cancer cell migration. As footprint deposition increases with substrate rigidity, these cues can regulate stiffness-guided directional cell migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  181. Fan, C. et al. Cell migration orchestrates migrasome formation by shaping retraction fibers. J. Cell Biol. 221, e202109168 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  182. 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).

    Article  CAS  PubMed  Google Scholar 

  183. Yamada, K. M., Doyle, A. D. & Lu, J. Cell–3D matrix interactions: recent advances and opportunities. Trends Cell Biol. 32, 883–895 (2022).

    Article  CAS  PubMed  Google Scholar 

  184. Nazari, S. S., Doyle, A. D. & Yamada, K. M. Mechanisms of basement membrane micro-perforation during cancer cell invasion into a 3D collagen gel. Gels 8, 567 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  185. Nazari, S. S., Doyle, A. D., Bleck, C. K. E. & Yamada, K. M. Long prehensile protrusions can facilitate cancer cell invasion through the basement membrane. Cells 12, 2474 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  PubMed  PubMed Central  Google Scholar 

  187. Peuhu, E. et al. MYO10-filopodia support basement membranes at pre-invasive tumor boundaries. Dev. Cell 57, 2350–2364.e7 (2022).

    Article  CAS  PubMed  Google Scholar 

  188. Chang, J. et al. Cell volume expansion and local contractility drive collective invasion of the basement membrane in breast cancer. Nat. Mater. 23, 711–722 (2024).

    Article  CAS  PubMed  Google Scholar 

  189. Mustafa, S., Koran, S. & AlOmair, L. Insights into the role of matrix metalloproteinases in cancer and its various therapeutic aspects: a review. Front. Mol. Biosci. 9, 896099 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  190. Yue, J., Zhang, K. & Chen, J. Role of integrins in regulating proteases to mediate extracellular matrix remodeling. Cancer Microenviron. 5, 275–283 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  191. Niland, S. & Eble, J. A. Hold on or cut? Integrin- and MMP-mediated cell–matrix interactions in the tumor microenvironment. Int. J. Mol. Sci. 22, 238 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  192. Mori, H. et al. Transmembrane/cytoplasmic, rather than catalytic, domains of Mmp14 signal to MAPK activation and mammary branching morphogenesis via binding to integrin β1. Development 140, 343–352 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  193. Grafinger, O. R., Gorshtein, G., Stirling, T., Brasher, M. I. & Coppolino, M. G. β1 integrin-mediated signaling regulates MT1-MMP phosphorylation to promote tumor cell invasion. J. Cell Sci. 133, jcs239152 (2020).

    Article  CAS  PubMed  Google Scholar 

  194. Grafinger, O. R., Gorshtein, G., Stirling, T., Geddes-McAlister, J. & Coppolino, M. G. Inhibition of β1 integrin induces its association with MT1-MMP and decreases MT1-MMP internalization and cellular invasiveness. Cell. Signal. 83, 109984 (2021).

    Article  CAS  PubMed  Google Scholar 

  195. Longmate, W. M., Miskin, R. P., Van De Water, L. & DiPersio, C. M. Epidermal integrin α3β1 regulates tumor-derived proteases BMP-1, matrix metalloprotease-9, and matrix metalloprotease-3. JID Innov. 1, 100017 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  196. Afshar, K., Sanaei, M., Ravari, M. S., Pourbagheri‐Sigaroodi, A. & Bashash, D. An overview of extracellular matrix and its remodeling in the development of cancer and metastasis with a glance at therapeutic approaches. Cell Biochem. Funct. 41, 930–952 (2023).

    Article  CAS  PubMed  Google Scholar 

  197. Niland, S., Riscanevo, A. X. & Eble, J. A. Matrix metalloproteinases shape the tumor microenvironment in cancer progression. Int. J. Mol. Sci. 23, 146 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  198. Kwon, Y. et al. Multi-layered proteogenomic analysis unravels cancer metastasis directed by MMP-2 and focal adhesion kinase signaling. Sci. Rep. 11, 17130 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  199. Linder, S., Wiesner, C. & Himmel, M. Degrading devices: invadosomes in proteolytic cell invasion. Annu. Rev. Cell Dev. Biol. 27, 185–211 (2011).

    Article  CAS  PubMed  Google Scholar 

  200. Monteiro, P. et al. A mechanosensitive caveolae–invadosome interplay drives matrix remodelling for cancer cell invasion. Nat. Cell Biol. 25, 1787–1803 (2023). This study describes a new mechanism of cancer cell-mediated collagen matrix remodelling through juxtaposed caveola clusters and matrix-degradative invadosomes at contact sites between the plasma membrane of cancer cells and collagen fibres.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  201. Jiao, Y. et al. Matrix metalloproteinase-2 promotes αvβ3 integrin-mediated adhesion and migration of human melanoma cells by cleaving fibronectin. PLoS ONE 7, e41591 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  202. Das, A., Monteiro, M., Barai, A., Kumar, S. & Sen, S. MMP proteolytic activity regulates cancer invasiveness by modulating integrins. Sci. Rep. 7, 14219 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  203. Labernadie, A. et al. A mechanically active heterotypic E-cadherin/N-cadherin adhesion enables fibroblasts to drive cancer cell invasion. Nat. Cell Biol. 19, 224–237 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  204. Gaggioli, C. et al. Fibroblast-led collective invasion of carcinoma cells with differing roles for RhoGTPases in leading and following cells. Nat. Cell Biol. 9, 1392–1400 (2007).

    Article  CAS  PubMed  Google Scholar 

  205. Carey, S. P., Starchenko, A., McGregor, A. L. & Reinhart-King, C. A. Leading malignant cells initiate collective epithelial cell invasion in a three-dimensional heterotypic tumor spheroid model. Clin. Exp. Metastasis 30, 615–630 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  206. Cheung, K. J., Gabrielson, E., Werb, Z. & Ewald, A. J. Collective invasion in breast cancer requires a conserved basal epithelial program. Cell 155, 1639–1651 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  207. Westcott, J. M. et al. An epigenetically distinct breast cancer cell subpopulation promotes collective invasion. J. Clin. Invest. 125, 1927–1943 (2015).

    Article  PubMed  PubMed Central  Google Scholar 

  208. Lichtenberg, J. Y. et al. Leader cells mechanically respond to aligned collagen architecture to direct collective migration. PLoS ONE 19, e0296153 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  209. Jacquemet, G. et al. FiloQuant reveals increased filopodia density during breast cancer progression. J. Cell Biol. 216, 3387–3403 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  210. Pekkonen, P. et al. Lymphatic endothelium stimulates melanoma metastasis and invasion via MMP14-dependent Notch3 and β1-integrin activation. eLife 7, e32490 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  211. Yamaguchi, N., Mizutani, T., Kawabata, K. & Haga, H. Leader cells regulate collective cell migration via Rac activation in the downstream signaling of integrin β1 and PI3K. Sci. Rep. 5, 7656 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  212. Attieh, Y. et al. Cancer-associated fibroblasts lead tumor invasion through integrin-β3-dependent fibronectin assembly. J. Cell Biol. 216, 3509–3520 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  214. Summerbell, E. R. et al. Epigenetically heterogeneous tumor cells direct collective invasion through filopodia-driven fibronectin micropatterning. Sci. Adv. 6, eaaz6197 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  215. Arjonen, A. et al. Mutant p53-associated myosin-X upregulation promotes breast cancer invasion and metastasis. J. Clin. Invest. 124, 1069–1082 (2014).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  216. Hwang, P. Y. et al. A Cdh3–β-catenin–laminin signaling axis in a subset of breast tumor leader cells control leader cell polarization and directional collective migration. Dev. Cell 58, 34–50.e9 (2023). This study investigates breast tumour organoid invasion into stroma using a 3D microfluidic system and 3D computational models, and demonstrates that leader cells generate their own laminin–IAC gradient and high protrusive forces to invade and overcome ECM resistance.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  217. Ferrari, R. et al. MT1-MMP directs force-producing proteolytic contacts that drive tumor cell invasion. Nat. Commun. 10, 4886 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  218. Sung, B. H., Parent, C. A. & Weaver, A. M. Extracellular vesicles: critical players during cell migration. Dev. Cell 56, 1861–1874 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  219. Friedl, P. et al. Migration of highly aggressive MV3 melanoma cells in 3-dimensional collagen lattices results in local matrix reorganization and shedding of ɑ2 and β1 integrins and CD44. Cancer Res. 57, 2061–2070 (1997).

    CAS  PubMed  Google Scholar 

  220. Sung, B. H. et al. A live cell reporter of exosome secretion and uptake reveals pathfinding behavior of migrating cells. Nat. Commun. 11, 2092 (2020). This study uses an improved live cell reporter to visualize secreted exosomes in 3D culture and in vivo, and identifies a role for exosomes in promoting leader–follower behaviour in 2D and 3D migration.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  221. Sung, B. H., Ketova, T., Hoshino, D., Zijlstra, A. & Weaver, A. M. Directional cell movement through tissues is controlled by exosome secretion. Nat. Commun. 6, 7164 (2015).

    Article  CAS  PubMed  Google Scholar 

  222. Jehanno, C., Vulin, M., Richina, V., Richina, F. & Bentires-Alj, M. Phenotypic plasticity during metastatic colonization. Trends Cell Biol. 32, 854–867 (2022).

    Article  PubMed  Google Scholar 

  223. Massagué, J. & Obenauf, A. C. Metastatic colonization by circulating tumour cells. Nature 529, 298–306 (2016).

    Article  PubMed  PubMed Central  Google Scholar 

  224. Gassmann, P., Hemping-Bovenkerk, A., Mees, S. T. & Haier, J. Metastatic tumor cell arrest in the liver–lumen occlusion and specific adhesion are not exclusive. Int. J. Colorectal Dis. 24, 851–858 (2009).

    Article  PubMed  Google Scholar 

  225. Schlesinger, M. & Bendas, G. Contribution of very late antigen-4 (VLA-4) integrin to cancer progression and metastasis. Cancer Metastasis Rev. 34, 575–591 (2015).

    Article  CAS  PubMed  Google Scholar 

  226. Follain, G. et al. Hemodynamic forces tune the arrest, adhesion, and extravasation of circulating tumor cells. Dev. Cell 45, 33–52.e12 (2018).

    Article  CAS  PubMed  Google Scholar 

  227. Osmani, N. et al. Metastatic tumor cells exploit their adhesion repertoire to counteract shear forces during intravascular arrest. Cell Rep. 28, 2491–2500.e5 (2019). This study establishes a step-wise mechanism of circulating tumour cell attachment to the endothelium and extravasation, whereby, during early arrest, weaker adhesion is mediated by CD44 and αvβ3 integrin, and adhesion strengthening and stabilization is mediated by α5β1 integrin adhesion to luminally deposited fibronectin on endothelial cells.

    Article  CAS  PubMed  Google Scholar 

  228. Paul, C. D. et al. Tissue architectural cues drive organ targeting of tumor cells in zebrafish. Cell Syst. 9, 187–206.e16 (2019).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  229. Ward, J. & Martin, P. Live-imaging studies reveal how microclots and the associated inflammatory response enhance cancer cell extravasation. J. Cell Sci. 136, jcs261225 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  230. Kienast, Y. et al. Real-time imaging reveals the single steps of brain metastasis formation. Nat. Med. 16, 116–122 (2010).

    Article  CAS  PubMed  Google Scholar 

  231. Garcia-Leon, M. J. et al. Platelets favor the outgrowth of established metastases. Nat. Commun. 15, 3297 (2024).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  232. Yoneda, T., Williams, P. J., Hiraga, T., Niewolna, M. & Nishimura, R. A bone-seeking clone exhibits different biological properties from the MDA-MB-231 parental human breast cancer cells and a brain-seeking clone in vivo and in vitro. J. Bone Miner. Res. 16, 1486–1495 (2001).

    Article  CAS  PubMed  Google Scholar 

  233. Carbonell, W. S., Ansorge, O., Sibson, N. & Muschel, R. The vascular basement membrane as “soil” in brain metastasis. PLoS One 4, e5857 (2009).

    Article  PubMed  PubMed Central  Google Scholar 

  234. Zhang, L. et al. EZH2 engages TGFβ signaling to promote breast cancer bone metastasis via integrin β1-FAK activation. Nat. Commun. 13, 2543 (2022). This work establishes a feedforward loop of the EZH2–β1 integrin–FAK axis cooperating with the TGFβ signalling pathway to promote bone metastasis of breast cancer.

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  235. Li, X. Q., Zhang, R., Lu, H., Yue, X. M. & Huang, Y. F. Extracellular vesicle-packaged CDH11 and ITGA5 induce the premetastatic niche for bone colonization of breast cancer cells. Cancer Res. 82, 1560–1574 (2022).

    Article  CAS  PubMed  Google Scholar 

  236. Lau, D. et al. Role of c-Met/β1 integrin complex in the metastatic cascade in breast cancer. JCI Insight 6, e138928 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  237. Pantano, F. et al. Integrin ɑ5 in human breast cancer is a mediator of bone metastasis and a therapeutic target for the treatment of osteolytic lesions. Oncogene 40, 1284–1299 (2021).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  238. Huang, Y.-L. L. et al. Collagen-rich omentum is a premetastatic niche for integrin α2-mediated peritoneal metastasis. eLife 9, 1–34 (2020).

    Article  Google Scholar 

  239. Miyamoto, S. et al. Integrin α5 mediates cancer cell-fibroblast adhesion and peritoneal dissemination of diffuse-type gastric carcinoma. Cancer Lett. 526, 335–345 (2022).

    Article  CAS  PubMed  Google Scholar 

  240. Howe, E. N. et al. Rab11b-mediated integrin recycling promotes brain metastatic adaptation and outgrowth. Nat. Commun. 11, 3017 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  241. Hoshino, A. et al. Tumour exosome integrins determine organotropic metastasis. Nature 527, 329–335 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  242. Pang, X. et al. Targeting integrin pathways: mechanisms and advances in therapy. Signal Transduct. Target. Ther. 8, 1 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  243. Slack, R. J., Macdonald, S. J. F. F., Roper, J. A., Jenkins, R. G. & Hatley, R. J. D. D. Emerging therapeutic opportunities for integrin inhibitors. Nat. Rev. Drug. Discov. 21, 60–78 (2022).

    Article  CAS  PubMed  Google Scholar 

  244. Orré, T. et al. Molecular motion and tridimensional nanoscale localization of kindlin control integrin activation in focal adhesions. Nat. Commun. 12, 3104 (2021).

    Article  PubMed  PubMed Central  Google Scholar 

  245. Hoffmann, J.-E. et al. Symmetric exchange of multi-protein building blocks between stationary focal adhesions and the cytosol. eLife 3, e02257 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  246. Shi, M. et al. Latent TGF-β structure and activation. Nature 474, 343–349 (2011).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  247. Mu, D. et al. The integrin αvβ8 mediates epithelial homeostasis through MT1-MMP-dependent activation of TGF-β1. J. Cell Biol. 157, 493–507 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  248. Dong, X. et al. Force interacts with macromolecular structure in activation of TGF-β. Nature 542, 55–59 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  249. Magnussen, S. N. et al. Nephronectin promotes breast cancer brain metastatic colonization via its integrin-binding domains. Sci. Rep. 10, 12237 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  250. Khalil, A. A. & de Rooij, J. Cadherin mechanotransduction in leader–follower cell specification during collective migration. Exp. Cell Res. 376, 86–91 (2019).

    Article  CAS  PubMed  Google Scholar 

  251. Arjonen, A., Alanko, J., Veltel, S. & Ivaska, J. Distinct recycling of active and inactive β1 integrins. Traffic 13, 610–625 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  252. Shafaq-Zadah, M. et al. Persistent cell migration and adhesion rely on retrograde transport of β1 integrin. Nat. Cell Biol. 18, 54–64 (2016).

    Article  CAS  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  254. 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).

    Article  PubMed  PubMed Central  Google Scholar 

  255. Yu, C. et al. Integrin-β3 clusters recruit clathrin-mediated endocytic machinery in the absence of traction force. Nat. Commun. 6, 8672 (2015).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  256. Teckchandani, A. et al. Quantitative proteomics identifies a Dab2/integrin module regulating cell migration. J. Cell Biol. 186, 99–111 (2009).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  257. Lakshminarayan, R. et al. Galectin-3 drives glycosphingolipid-dependent biogenesis of clathrin-independent carriers. Nat. Cell Biol. 16, 592–603 (2014).

    Article  Google Scholar 

  258. Sabharanjak, S., Sharma, P., Parton, R. G. & Mayor, S. GPI-anchored proteins are delivered to recycling endosomes via a distinct cdc42-regulated, clathrin-independent pinocytic pathway. Dev. Cell 2, 411–423 (2002).

    Article  CAS  PubMed  Google Scholar 

  259. Kumari, S. & Mayor, S. ARF1 is directly involved in dynamin-independent endocytosis. Nat. Cell Biol. 10, 30–41 (2008).

    Article  CAS  PubMed  Google Scholar 

  260. 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).

    Article  CAS  PubMed  Google Scholar 

  261. Barrow-McGee, R. et al. β1-Integrin–c-Met cooperation reveals an inside-in survival signalling on autophagy-related endomembranes. Nat. Commun. 7, 11942 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  262. Bridgewater, R. E., Norman, J. C. & Caswell, P. T. Integrin trafficking at a glance. J. Cell Sci. 125, 3695–3701 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  263. Rainero, E. et al. Diacylglycerol kinase α controls RCP-dependent integrin trafficking to promote invasive migration. J. Cell Biol. 196, 277–295 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  264. Jacquemet, G. et al. RCP-driven α5β1 recycling suppresses Rac and promotes RhoA activity via the RacGAP1–IQGAP1 complex. J. Cell Biol. 202, 917–935 (2013).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  265. Muller, P. A. J. et al. Mutant p53 drives invasion by promoting integrin recycling. Cell 139, 1327–1341 (2009).

    Article  PubMed  Google Scholar 

  266. Caswell, P. T. et al. Rab25 associates with α5β1 integrin to promote invasive migration in 3D microenvironments. Dev. Cell 13, 496–510 (2007).

    Article  CAS  PubMed  Google Scholar 

  267. 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).

    Article  PubMed  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  269. Sahgal, P. et al. GGA2 and RAB13 promote activity-dependent β1-integrin recycling. J. Cell Sci. 132, jcs233387 (2019).

    Article  CAS  PubMed  Google Scholar 

  270. Dozynkiewicz, M. A. et al. Rab25 and CLIC3 collaborate to promote integrin recycling from late endosomes/lysosomes and drive cancer progression. Dev. Cell 22, 131–145 (2012).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  271. Wickstrom, S. A., Radovanac, K. & Fassler, R. Genetic analyses of integrin signaling. Cold Spring Harb. Perspect. Biol. 3, a005116 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  272. Walma, D. A. C. & Yamada, K. M. The extracellular matrix in development. Development 147, dev175596 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  273. Leonard, C. E. & Taneyhill, L. A. The road best traveled: neural crest migration upon the extracellular matrix. Semin. Cell Dev. Biol. 100, 177–185 (2020).

    Article  CAS  PubMed  Google Scholar 

  274. McKeown, S. J., Wallace, A. S. & Anderson, R. B. Expression and function of cell adhesion molecules during neural crest migration. Dev. Biol. 373, 244–257 (2013).

    Article  CAS  PubMed  Google Scholar 

  275. Mittal, A., Pulina, M., Hou, S.-Y. & Astrof, S. Fibronectin and integrin α5 play essential roles in the development of the cardiac neural crest. Mech. Dev. 127, 472–484 (2010).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  276. Ma, S. et al. Developmentally regulated expression of integrin α6 distinguishes neural crest derivatives in the skin. Front. Cell Dev. Biol. 11, 1140554 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  277. Thomas, R., Menon, V., Mani, R. & Pruszak, J. Glycan epitope and integrin expression dynamics characterize neural crest epithelial-to-mesenchymal transition (EMT) in human pluripotent stem cell differentiation. Stem Cell Rev. Rep. 18, 2952–2965 (2022).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  278. Li, X. et al. Integrin αvβ3 mediates K1735 murine melanoma cell motility in vivo and in vitro. J. Cell Sci. 114, 2665–2672 (2001).

    Article  CAS  PubMed  Google Scholar 

  279. Hsu, M.-Y. et al. Adenoviral gene transfer of β3 integrin subunit induces conversion from radial to vertical growth phase in primary human melanoma. Am. J. Pathol. 153, 1435–1442 (1998).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  280. Shaw, T. J. & Martin, P. Wound repair: a showcase for cell plasticity and migration. Curr. Opin. Cell Biol. 42, 29–37 (2016).

    Article  CAS  PubMed  Google Scholar 

  281. Watt, F. M. New EMBO Member’s Review: role of integrins in regulating epidermal adhesion, growth and differentiation. EMBO J. 21, 3919–3926 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  282. Juhasz, I., Murphy, G. F., Yan, H. C., Herlyn, M. & Albelda, S. M. Regulation of extracellular matrix proteins and integrin cell substratum adhesion receptors on epithelium during cutaneous human wound healing in vivo. Am. J. Pathol. 143, 1458–1469 (1993).

    CAS  PubMed  PubMed Central  Google Scholar 

  283. Koivisto, L., Heino, J., Häkkinen, L. & Larjava, H. Integrins in wound healing. Adv. Wound Care 3, 762–783 (2014).

    Article  Google Scholar 

  284. Geuijen, C. A. W. & Sonnenberg, A. Dynamics of the α6β4 integrin in keratinocytes. Mol. Biol. Cell 13, 3845–3858 (2002).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  285. Nakayama, Y. et al. Blockade of interaction of α9 integrin with its ligands hinders the formation of granulation in cutaneous wound healing. Lab. Invest. 90, 881–894 (2010).

    Article  CAS  PubMed  Google Scholar 

  286. Frisch, S. & Francis, H. Disruption of epithelial cell–matrix interactions induces apoptosis. J. Cell Biol. 124, 619–626 (1994).

    Article  CAS  PubMed  Google Scholar 

  287. Vachon, P. H. Integrin signaling, cell survival, and anoikis: distinctions, differences, and differentiation. J. Signal. Transduct. 2011, 1–18 (2011).

    Article  Google Scholar 

  288. Stupack, D. G., Puente, X. S., Boutsaboualoy, S., Storgard, C. M. & Cheresh, D. A. Apoptosis of adherent cells by recruitment of caspase-8 to unligated integrins. J. Cell Biol. 155, 459–470 (2001).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  289. Frisch, S. M. et al. Control of adhesion-dependent cell survival by focal adhesion kinase. J. Cell Biol. 134, 793–799 (1996).

    Article  CAS  PubMed  Google Scholar 

  290. Frisch, S. M. & Screaton, R. A. Anoikis mechanisms. Curr. Opin. Cell Biol. 13, 555–562 (2001).

    Article  CAS  PubMed  Google Scholar 

  291. Garnett, H. M. A scanning electron microscope study of the sequential changes in morphology occuring in human fibroblasts placed in suspension culture. Cytobios 27, 7–18 (1980).

    CAS  PubMed  Google Scholar 

  292. Bridges, A. A., Jentzsch, M. S., Oakes, P. W., Occhipinti, P. & Gladfelter, A. S. Micron-scale plasma membrane curvature is recognized by the septin cytoskeleton. J. Cell Biol. 213, 23–32 (2016).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  293. Weems, A. D. et al. Blebs promote cell survival by assembling oncogenic signalling hubs. Nature 615, 517–525 (2023).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  294. Zimmermann, K. C., Bonzon, C. & Green, D. R. The machinery of programmed cell death. Pharmacol. Ther. 92, 57–70 (2001).

    Article  CAS  PubMed  Google Scholar 

  295. Ward, K. K. et al. Inhibition of focal adhesion kinase (FAK) activity prevents anchorage-independent ovarian carcinoma cell growth and tumor progression. Clin. Exp. Metastasis 30, 579–594 (2013).

    Article  CAS  PubMed  Google Scholar 

  296. Demers, M.-J. et al. Intestinal epithelial cancer cell anoikis resistance: EGFR-mediated sustained activation of Src overrides Fak-dependent signaling to MEK/Erk and/or PI3-K/Akt-1. J. Cell. Biochem. 107, 639–654 (2009).

    Article  CAS  PubMed  Google Scholar 

  297. Bertotti, A., Comoglio, P. M. & Trusolino, L. β4 integrin activates a Shp2–Src signaling pathway that sustains HGF-induced anchorage-independent growth. J. Cell Biol. 175, 993–1003 (2006).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  298. George, S., Martin, J. A. J., Graziani, V. & Sanz-Moreno, V. Amoeboid migration in health and disease: immune responses versus cancer dissemination. Front. Cell Dev. Biol. 10, 1091801 (2023).

    Article  PubMed  PubMed Central  Google Scholar 

  299. Seguin, L. et al. Galectin-3, a druggable vulnerability for KRAS-addicted cancers. Cancer Discov. 7, 1464–1479 (2017).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  300. Ubellacker, J. M. et al. Lymph protects metastasizing melanoma cells from ferroptosis. Nature 585, 113–118 (2020).

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Acknowledgements

The authors thank H. Hamidi for critical reading of the manuscript and the members of the Ivaska laboratory for helpful discussions. M. Humphries is acknowledged for insightful comments and advice. This work was supported by the Finnish Cancer Institute (K. Albin Johansson Professorship, to J.I.); a Research Council of Finland Centre of Excellence programme, Biological Barrier Mechanics and Disease (346131 and 364182, to J.I.); the Cancer Foundation Finland (to J.I.); the Sigrid Juselius Foundation (to J.I.); the Research Council of Finland’s Flagship InFLAMES (337530 and 357910); the Jane and Aatos Erkko Foundation (to J.I.); a Research Council of Finland postdoctoral research grant (343239, to M.R.C.); the Turku Doctoral Programme of Molecular Medicine (TuDMM) (to J.K.); and the Finnish Cultural Foundation (to J.K.).

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  1. These authors contributed equally: Megan R. Chastney, Jasmin Kaivola.

Authors and Affiliations

  1. Turku Bioscience Centre, University of Turku and Åbo Akademi University, Turku, Finland

    Megan R. Chastney, Jasmin Kaivola, Veli-Matti Leppänen & Johanna Ivaska

  2. Department of Life Technologies, University of Turku, Turku, Finland

    Johanna Ivaska

  3. InFLAMES Research Flagship Center, University of Turku, Turku, Finland

    Johanna Ivaska

  4. Western Finnish Cancer Center (FICAN West), University of Turku, Turku, Finland

    Johanna Ivaska

  5. Foundation for the Finnish Cancer Institute, Helsinki, Finland

    Johanna Ivaska

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Glossary

Cancer-associated fibroblasts

(CAFs). Specialized fibroblasts with pro-tumorigenic functions such as extracellular matrix (ECM) remodelling that are found in the tumour microenvironment.

Catch bonds

Bonds between proteins that have an increased lifetime when force is applied. Catch bonds between integrins and ligands have an important role in mechanotransduction.

Caveolae

Small pits or invaginations at the plasma membrane containing proteins such as caveolin and cavin. Caveolae budding off from the membrane form endocytic vesicles.

Clathrin

A scaffolding protein that forms cage-like structures at the membrane, either as flat lattices or clathrin-coated pits. Clathrin-coated vesicles enable selective sorting of cargo via adaptors.

Extracellular matrix

(ECM). A network of proteoglycans and fibrous proteins providing structural support for cells and facilitating differentiation, proliferation and adhesion.

Filopodia

Thin, finger-like actin protrusions that extend from the cell leading edge that probe the surrounding environment and are stabilized by integrin engagement to the substrate.

Filopodial adhesions

A type of integrin adhesion complex (IAC) found at the tips of filopodia.

Focal adhesion kinase

(FAK). A tyrosine kinase that mediates integrin signalling.

Invadopodia

Actin-rich protrusions containing integrins employed by cancer cells that bind to components of the extracellular matrix (ECM) and facilitate their proteolytic degradation.

Lamellipodia

Wide, sheet-like protrusions driven by branched actin polymerization and located at the leading edge of a moving cell.

Lamellum

Actin-rich region of the cell behind lamellipodia, which is less dynamic than lamellipodia.

Podosomes

Similar to invadopodia, podosomes facilitate proteolytic degradation of the extracellular matrix (ECM). Podosomes consist of a ring of integrins with an actin-dense core.

Reticular adhesions

An integrin adhesion complex (IAC) subtype that is enriched in β5 integrin, clathrin and endocytic adaptors, but lacks many typical adhesome components. Also known as flat clathrin lattices or clathrin plaques.

Src

A non-receptor tyrosine kinase (non-RTK) that localizes to and regulates integrin adhesion complexes (IACs), for example through phosphorylation of focal adhesion kinase (FAK).

TGFβ

(Transforming growth factor receptor-β). A cytokine that regulates cellular processes such as proliferation, differentiation and apoptosis, and is a key inducer of epithelial–mesenchymal transition (EMT).

Viscoelastic

A property of a material that has both viscous and elastic properties. These materials have characteristics of both a liquid and a solid, with a time-dependent response to force.

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Chastney, M.R., Kaivola, J., Leppänen, VM. et al. The role and regulation of integrins in cell migration and invasion. Nat Rev Mol Cell Biol 26, 147–167 (2025). https://doi.org/10.1038/s41580-024-00777-1

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