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The principles of directed cell migration

Abstract

Cells have the ability to respond to various types of environmental cues, and in many cases these cues induce directed cell migration towards or away from these signals. How cells sense these cues and how they transmit that information to the cytoskeletal machinery governing cell translocation is one of the oldest and most challenging problems in biology. Chemotaxis, or migration towards diffusible chemical cues, has been studied for more than a century, but information is just now beginning to emerge about how cells respond to other cues, such as substrate-associated cues during haptotaxis (chemical cues on the surface), durotaxis (mechanical substrate compliance) and topotaxis (geometric features of substrate). Here we propose four common principles, or pillars, that underlie all forms of directed migration. First, a signal must be generated, a process that in physiological environments is much more nuanced than early studies suggested. Second, the signal must be sensed, sometimes by cell surface receptors, but also in ways that are not entirely clear, such as in the case of mechanical cues. Third, the signal has to be transmitted from the sensing modules to the machinery that executes the actual movement, a step that often requires amplification. Fourth, the signal has to be converted into the application of asymmetric force relative to the substrate, which involves mostly the cytoskeleton, but perhaps other players as well. Use of these four pillars has allowed us to compare some of the similarities between different types of directed migration, but also to highlight the remarkable diversity in the mechanisms that cells use to respond to different cues provided by their environment.

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Fig. 1: Generating the signal.
Fig. 2: Sensing the signal.
Fig. 3: Transmitting the signal.
Fig. 4: Executing the signal.

References

  1. 1.

    Borrell, V. Recent advances in understanding neocortical development. F1000Res https://doi.org/10.12688/f1000research.20332.1 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  2. 2.

    Pawar, K. B., Desai, S., Bhonde, R. R., Bhole, R. P. & Deshmukh, A. A. Wound with diabetes: present scenario and future. Curr. Diabetes Rev. https://doi.org/10.2174/1573399816666200703180137 (2020).

    Article  Google Scholar 

  3. 3.

    Janssen, E. & Geha, R. S. Primary immunodeficiencies caused by mutations in actin regulatory proteins. Immunol. Rev. 287, 121–134 (2019).

    CAS  PubMed  Article  Google Scholar 

  4. 4.

    Novikov, N. M., Zolotaryova, S. Y., Gautreau, A. M. & Denisov, E. V. Mutational drivers of cancer cell migration and invasion. Br. J. Cancer https://doi.org/10.1038/s41416-020-01149-0 (2020).

    Article  PubMed  Google Scholar 

  5. 5.

    García-Cuesta, E. M. et al. The role of the CXCL12/CXCR4/ACKR3 axis in autoimmune diseases. Front. Endocrinol. 10, 585 (2019).

    Article  Google Scholar 

  6. 6.

    Glass, D. S. et al. Idiopathic pulmonary fibrosis: molecular mechanisms and potential treatment approaches. Respir Investig. 58, 320–335 (2020).

    PubMed  Article  Google Scholar 

  7. 7.

    Abercrombie, M. The Croonian Lecture, 1978 - the crawling movement of metazoan cells. Proc. Royal Soc. B Biol. Sci. 207, 129–147 (1980).

    Google Scholar 

  8. 8.

    Abercrombie, M., Dunn, G. A. & Heath, J. P. The shape and movement of fibroblasts in culture. Soc. Gen. Physiol. Ser. 32, 57–70 (1977).

    CAS  PubMed  Google Scholar 

  9. 9.

    Sardelli, L. et al. Engineering biological gradients. J. Appl. Biomater. Funct. Mater. 17, 2280800019829023 (2019).

    CAS  PubMed  Google Scholar 

  10. 10.

    Buttenschön, A. & Edelstein-Keshet, L. Bridging from single to collective cell migration: a review of models and links to experiments. PLoS Comput. Biol. 16, e1008411 (2020).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  11. 11.

    Wilkinson, P. C. Random locomotion; chemotaxis and chemokinesis. a guide to terms defining cell locomotion. Immunol. Today 6, 273–278 (1985).

    CAS  PubMed  Article  Google Scholar 

  12. 12.

    Petrie, R. J., Doyle, A. D. & Yamada, K. M. Random versus directionally persistent cell migration. Nat. Rev. Mol. Cell Biol. 10, 538–549 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  13. 13.

    Dorward, D. A. et al. The role of formylated peptides and formyl peptide receptor 1 in governing neutrophil function during acute inflammation. Am. J. Pathol. 185, 1172–1184 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  14. 14.

    Ehrengruber, M. U., Geiser, T. & Deranleau, D. A. Activation of human neutrophils by C3a and C5A. Comparison of the effects on shape changes, chemotaxis, secretion, and respiratory burst. FEBS Lett. 346, 181–184 (1994).

    CAS  PubMed  Article  Google Scholar 

  15. 15.

    Sadik, C. D. & Luster, A. D. Lipid-cytokine-chemokine cascades orchestrate leukocyte recruitment in inflammation. J. Leukoc. Biol. 91, 207–215 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  16. 16.

    McDonald, B. & Kubes, P. Cellular and molecular choreography of neutrophil recruitment to sites of sterile inflammation. J. Mol. Med. 89, 1079–1088 (2011).

    CAS  PubMed  Article  Google Scholar 

  17. 17.

    Junger, W. G. Immune cell regulation by autocrine purinergic signalling. Nat. Rev. Immunol. 11, 201–212 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  18. 18.

    Yoo, S. K., Starnes, T. W., Deng, Q. & Huttenlocher, A. Lyn is a redox sensor that mediates leukocyte wound attraction in vivo. Nature 480, 109–112 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  19. 19.

    Katikaneni, A. et al. Lipid peroxidation regulates long-range wound detection through 5-lipoxygenase in zebrafish. Nat. Cell Biol. 22, 1049–1055 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  20. 20.

    Blockus, H. & Chédotal, A. Slit-Robo signaling. Development 143, 3037–3044 (2016).

    CAS  PubMed  Article  Google Scholar 

  21. 21.

    Boyer, N. P. & Gupton, S. L. Revisiting netrin-1: one who guides (axons). Front. Cell Neurosci. 12, 221 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  22. 22.

    Hu, S. & Zhu, L. Semaphorins and their receptors: from axonal guidance to atherosclerosis. Front. Physiol. 9, 1236 (2018).

    PubMed  PubMed Central  Google Scholar 

  23. 23.

    Kania, A. & Klein, R. Mechanisms of ephrin-Eph signalling in development, physiology and disease. Nat. Rev. Mol. Cell Biol. 17, 240–256 (2016).

    CAS  PubMed  Article  Google Scholar 

  24. 24.

    Crick, F. Diffusion in embryogenesis. Nature 225, 420–422 (1970).

    CAS  PubMed  Article  Google Scholar 

  25. 25.

    Majumdar, R., Sixt, M. & Parent, C. A. New paradigms in the establishment and maintenance of gradients during directed cell migration. Curr. Opin. Cell Biol. 30, 33–40 (2014).

    CAS  PubMed  Article  Google Scholar 

  26. 26.

    Lau, S. et al. A negative-feedback loop maintains optimal chemokine concentrations for directional cell migration. Nat. Cell Biol. 22, 266–273 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  27. 27.

    Stapornwongkul, K. S., de Gennes, M., Cocconi, L., Salbreux, G. & Vincent, J. P. Patterning and growth control in vivo by an engineered GFP gradient. Science 370, 321–327 (2020). Using a synthetic morphogen in D. melanogaster, the authors show that the expression of non-signalling decoy receptors improves the ability of receptors engineered to respond to the synthetic morphogen to organize patterning and growth in vivo.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  28. 28.

    Tweedy, L., Knecht, D. A., Mackay, G. M. & Insall, R. H. Self-generated chemoattractant gradients: attractant depletion extends the range and robustness of chemotaxis. PLoS Biol. 14, e1002404 (2016).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  29. 29.

    Muinonen-Martin, A. J. et al. Melanoma cells break down LPA to establish local gradients that drive chemotactic dispersal. PLoS Biol. 12, e1001966 (2014).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  30. 30.

    Juin, A. et al. N-WASP control of LPAR1 trafficking establishes response to self-generated LPA gradients to promote pancreatic cancer cell metastasis. Dev. Cell https://doi.org/10.1016/j.devcel.2019.09.018 (2019).

    Article  PubMed  PubMed Central  Google Scholar 

  31. 31.

    Tweedy, L. et al. Seeing around corners: cells solve mazes and respond at a distance using attractant breakdown. Science https://doi.org/10.1126/science.aay9792 (2020).

    Article  PubMed  Google Scholar 

  32. 32.

    Pond, K. W., Doubrovinski, K. & Thorne, C. A. Wnt/β-catenin signaling in tissue self-organization. Genes (Basel) https://doi.org/10.3390/genes11080939 (2020).

    Article  Google Scholar 

  33. 33.

    Lu, P., Takai, K., Weaver, V. M. & Werb, Z. Extracellular matrix degradation and remodeling in development and disease. Cold Spring Harb. Perspect Biol. https://doi.org/10.1101/cshperspect.a005058 (2011).

    Article  PubMed  PubMed Central  Google Scholar 

  34. 34.

    Afonso, P. V., McCann, C. P., Kapnick, S. M. & Parent, C. A. Discoidin domain receptor 2 regulates neutrophil chemotaxis in 3D collagen matrices. Blood 121, 1644–1650 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  35. 35.

    Shields, J. D. et al. Autologous chemotaxis as a mechanism of tumor cell homing to lymphatics via interstitial flow and autocrine CCR7 signaling. Cancer Cell 11, 526–538 (2007).

    CAS  PubMed  Article  Google Scholar 

  36. 36.

    Polacheck, W. J., Charest, J. L. & Kamm, R. D. Interstitial flow influences direction of tumor cell migration through competing mechanisms. Proc. Natl Acad. Sci. USA 108, 11115–11120 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  37. 37.

    Müller, P., Rogers, K. W., Yu, S. R., Brand, M. & Schier, A. F. Morphogen transport. Development 140, 1621–1638 (2013).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  38. 38.

    Restrepo, S., Zartman, J. J. & Basler, K. Coordination of patterning and growth by the morphogen DPP. Curr. Biol. 24, R245–R255 (2014).

    CAS  PubMed  Article  Google Scholar 

  39. 39.

    Kriebel, P. W., Barr, V. A., Rericha, E. C., Zhang, G. & Parent, C. A. Collective cell migration requires vesicular trafficking for chemoattractant delivery at the trailing edge. J. Cell Biol. 183, 949–961 (2008).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  40. 40.

    Kriebel, P. W. et al. Extracellular vesicles direct migration by synthesizing and releasing chemotactic signals. J. Cell Biol. 217, 2891–2910 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  41. 41.

    Esser, J. et al. Exosomes from human macrophages and dendritic cells contain enzymes for leukotriene biosynthesis and promote granulocyte migration. J. Allergy Clin. Immunol. 126, 1032–1040 (2010).

    CAS  PubMed  Article  Google Scholar 

  42. 42.

    Afonso, P. V. et al. LTB4 is a signal-relay molecule during neutrophil chemotaxis. Dev. Cell 22, 1079–1091 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  43. 43.

    Lämmermann, T. et al. Neutrophil swarms require LTB4 and integrins at sites of cell death in vivo. Nature 498, 371–375 (2013).

    PubMed  Article  CAS  Google Scholar 

  44. 44.

    Brown, M. et al. Lymphatic exosomes promote dendritic cell migration along guidance cues. J. Cell. Biol. 217, 2205–2221 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  45. 45.

    Chen, T., Guo, J., Yang, M., Zhu, X. & Cao, X. Chemokine-containing exosomes are released from heat-stressed tumor cells via lipid raft-dependent pathway and act as efficient tumor vaccine. J. Immunol. 186, 2219–2228 (2011).

    CAS  PubMed  Article  Google Scholar 

  46. 46.

    Lim, K. et al. Neutrophil trails guide influenza-specific CD8+ T cells in the airways. Science 349, aaa4352 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  47. 47.

    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).

    CAS  PubMed  Article  Google Scholar 

  48. 48.

    Sung, B. H. & Weaver, A. M. Exosome secretion promotes chemotaxis of cancer cells. Cell Adh. Migr. 11, 187–195 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  49. 49.

    Hynes, R. O. Stretching the boundaries of extracellular matrix research. Nat. Rev. Mol. Cell Biol. 15, 761–763 (2014).

    CAS  PubMed  Article  Google Scholar 

  50. 50.

    Charras, G. & Sahai, E. Physical influences of the extracellular environment on cell migration. Nat. Rev. Mol. Cell Biol. 15, 813–824 (2014).

    CAS  PubMed  Article  Google Scholar 

  51. 51.

    Mouw, J. K., Ou, G. & Weaver, V. M. Extracellular matrix assembly: a multiscale deconstruction. Nat. Rev. Mol. Cell Biol. 15, 771–785 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  52. 52.

    Bonnans, C., Chou, J. & Werb, Z. Remodelling the extracellular matrix in development and disease. Nat. Rev. Mol. Cell Biol. 15, 786–801 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  53. 53.

    Albacete-Albacete, L. et al. ECM deposition is driven by caveolin-1-dependent regulation of exosomal biogenesis and cargo sorting. J. Cell Biol. https://doi.org/10.1083/jcb.202006178 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  54. 54.

    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).

    CAS  PubMed  PubMed Central  Google Scholar 

  55. 55.

    Singh, P., Carraher, C. & Schwarzbauer, J. E. Assembly of fibronectin extracellular matrix. Annu. Rev. Cell Dev. Biol. 26, 397–419 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  56. 56.

    Miller, C. G., Budoff, G., Prenner, J. L. & Schwarzbauer, J. E. Minireview: fibronectin in retinal disease. Exp. Biol. Med. 242, 1–7 (2017).

    CAS  Article  Google Scholar 

  57. 57.

    Schultz, G. S. & Wysocki, A. Interactions between extracellular matrix and growth factors in wound healing. Wound Repair Regen. 17, 153–162 (2009).

    PubMed  Article  Google Scholar 

  58. 58.

    Li, Q., Park, P. W., Wilson, C. L. & Parks, W. C. Matrilysin shedding of syndecan-1 regulates chemokine mobilization and transepithelial efflux of neutrophils in acute lung injury. Cell 111, 635–646 (2002).

    CAS  Article  Google Scholar 

  59. 59.

    Schumann, K. et al. Immobilized chemokine fields and soluble chemokine gradients cooperatively shape migration patterns of dendritic cells. Immunity 32, 703–713 (2010).

    CAS  PubMed  Article  Google Scholar 

  60. 60.

    Zhu, M. et al. Spatial mapping of tissue properties in vivo reveals a 3D stiffness gradient in the mouse limb bud. Proc. Natl Acad. Sci. USA 117, 4781–4791 (2020). This is a technical tour de force demonstrating the existence of stiffness gradients in mouse embryos.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  61. 61.

    Tran, V. D. & Kumar, S. Transduction of cell and matrix geometric cues by the actin cytoskeleton. Curr. Opin. Cell Biol. 68, 64–71 (2020).

    PubMed  Article  CAS  Google Scholar 

  62. 62.

    Cai, L., Xiong, X., Kong, X. & Xie, J. The role of the lysyl oxidases in tissue repair and remodeling: a concise review. Tissue Eng. Regen. Med. 14, 15–30 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  63. 63.

    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  Article  Google Scholar 

  64. 64.

    Ye, M. et al. Evolving roles of lysyl oxidase family in tumorigenesis and cancer therapy. Pharmacol. Ther. 215, 107633 (2020).

    CAS  PubMed  Article  Google Scholar 

  65. 65.

    Alcudia, J. F. et al. Lysyl oxidase and endothelial dysfunction: mechanisms of lysyl oxidase down-regulation by pro-inflammatory cytokines. Front. Biosci. 13, 2721–2727 (2008).

    CAS  PubMed  Article  Google Scholar 

  66. 66.

    Chen, Y., Peng, W., Raffetto, J. D. & Khalil, R. A. Matrix metalloproteinases in remodeling of lower extremity veins and chronic venous disease. Prog. Mol. Biol. Transl Sci. 147, 267–299 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  67. 67.

    Quintero-Fabián, S. et al. Role of matrix metalloproteinases in angiogenesis and cancer. Front. Oncol. 9, 1370 (2019).

    PubMed  PubMed Central  Article  Google Scholar 

  68. 68.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  69. 69.

    Paul, C. D., Mistriotis, P. & Konstantopoulos, K. Cancer cell motility: lessons from migration in confined spaces. Nat. Rev. Cancer 17, 131–140 (2017).

    CAS  PubMed  Article  Google Scholar 

  70. 70.

    Wolf, K., Müller, R., Borgmann, S., Bröcker, E. B. & Friedl, P. Amoeboid shape change and contact guidance: T-lymphocyte crawling through fibrillar collagen is independent of matrix remodeling by MMPs and other proteases. Blood 102, 3262–3269 (2003).

    CAS  PubMed  Article  Google Scholar 

  71. 71.

    Renkawitz, J. et al. Nuclear positioning facilitates amoeboid migration along the path of least resistance. Nature 568, 546–550 (2019). This seminal article shows that leukocytes position the nucleus frontwards to gauge the available space and choose their path.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  72. 72.

    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  Article  Google Scholar 

  73. 73.

    Wyckoff, J. B., Pinner, S. E., Gschmeissner, S., Condeelis, J. S. & Sahai, E. ROCK- and myosin-dependent matrix deformation enables protease-independent tumor-cell invasion in vivo. Curr. Biol. 16, 1515–1523 (2006).

    CAS  PubMed  Article  Google Scholar 

  74. 74.

    Fisher, K. E. et al. MT1-MMP- and Cdc42-dependent signaling co-regulate cell invasion and tunnel formation in 3D collagen matrices. J. Cell Sci. 122, 4558–4569 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  75. 75.

    Weigelin, B., Bakker, G. J. & Friedl, P. Intravital third harmonic generation microscopy of collective melanoma cell invasion: Principles of interface guidance and microvesicle dynamics. Intravital 1, 32–43 (2012).

    PubMed  Article  Google Scholar 

  76. 76.

    Du Bois-Reymond, E. H. Vorläufiger Abriss einer Untersuchung über den sogenannten Froschstrom und über die elektromotorischen Fische. Ann. Phys. https://doi.org/10.1002/andp.18431340102 (1843).

    Article  Google Scholar 

  77. 77.

    Zhao, M. et al. Electrical signals control wound healing through phosphatidylinositol-3-OH kinase-gamma and PTEN. Nature 442, 457–460 (2006).

    CAS  PubMed  Article  Google Scholar 

  78. 78.

    Hotary, K. B. & Robinson, K. R. Endogenous electrical currents and voltage gradients in Xenopus embryos and the consequences of their disruption. Dev. Biol. 166, 789–800 (1994).

    CAS  PubMed  Article  Google Scholar 

  79. 79.

    Klein, P. S. et al. A chemoattractant receptor controls development in Dictyostelium discoideum. Science 241, 1467–1472 (1988).

    CAS  PubMed  Article  Google Scholar 

  80. 80.

    Murphy, P. M. & Tiffany, H. L. Cloning of complementary DNA encoding a functional human interleukin-8 receptor. Science 253, 1280–1283 (1991).

    CAS  PubMed  Article  Google Scholar 

  81. 81.

    Holmes, W. E., Lee, J., Kuang, W. J., Rice, G. C. & Wood, W. I. Structure and functional expression of a human interleukin-8 receptor. Science 253, 1278–1280 (1991).

    CAS  PubMed  Article  Google Scholar 

  82. 82.

    Griffith, J. W., Sokol, C. L. & Luster, A. D. Chemokines and chemokine receptors: positioning cells for host defense and immunity. Annu. Rev. Immunol. 32, 659–702 (2014).

    CAS  PubMed  Article  Google Scholar 

  83. 83.

    Hughes, C. E. & Nibbs, R. J. B. A guide to chemokines and their receptors. FEBS J. 285, 2944–2971 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  84. 84.

    Zlotnik, A. & Yoshie, O. Chemokines: a new classification system and their role in immunity. Immunity 12, 121–127 (2000).

    CAS  Article  Google Scholar 

  85. 85.

    Sallusto, F. & Baggiolini, M. Chemokines and leukocyte traffic. Nat. Immunol. 9, 949–952 (2008).

    CAS  PubMed  Article  Google Scholar 

  86. 86.

    Locati, M. & Murphy, P. M. Chemokines and chemokine receptors: biology and clinical relevance in inflammation and AIDS. Annu. Rev. Med. 50, 425–440 (1999).

    CAS  PubMed  Article  Google Scholar 

  87. 87.

    Proudfoot, A. E. Chemokine receptors: multifaceted therapeutic targets. Nat. Rev. Immunol. 2, 106–115 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  88. 88.

    He, H. Q. & Ye, R. D. The formyl peptide receptors: diversity of ligands and mechanism for recognition. Molecules https://doi.org/10.3390/molecules22030455 (2017).

    Article  PubMed  PubMed Central  Google Scholar 

  89. 89.

    Yokomizo, T. Two distinct leukotriene B4 receptors, BLT1 and BLT2. J. Biochem. 157, 65–71 (2015).

    CAS  PubMed  Article  Google Scholar 

  90. 90.

    Sadik, C. D., Kim, N. D. & Luster, A. D. Neutrophils cascading their way to inflammation. Trends Immunol. 32, 452–460 (2011).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  91. 91.

    Anand-Apte, B. & Zetter, B. Signaling mechanisms in growth factor-stimulated cell motility. Stem Cells 15, 259–267 (1997).

    CAS  PubMed  Article  Google Scholar 

  92. 92.

    Vorotnikov, A. V. & Tyurin-Kuzmin, P. A. Chemotactic signaling in mesenchymal cells compared to amoeboid cells. Genes Dis. 1, 162–173 (2014).

    PubMed  PubMed Central  Article  Google Scholar 

  93. 93.

    Bear, J. E. & Haugh, J. M. Directed migration of mesenchymal cells: where signaling and the cytoskeleton meet. Curr. Opin. Cell Biol. 30, 74–82 (2014).

    CAS  PubMed  Article  Google Scholar 

  94. 94.

    Gorla, M. & Bashaw, G. J. Molecular mechanisms regulating axon responsiveness at the midline. Dev. Biol. 466, 12–21 (2020).

    CAS  PubMed  Article  Google Scholar 

  95. 95.

    Bellon, A. & Mann, F. Keeping up with advances in axon guidance. Curr. Opin. Neurobiol. 53, 183–191 (2018).

    CAS  PubMed  Article  Google Scholar 

  96. 96.

    Tessier-Lavigne, M. & Goodman, C. S. The molecular biology of axon guidance. Science 274, 1123–1133 (1996).

    CAS  PubMed  Article  Google Scholar 

  97. 97.

    Mirakaj, V. & Rosenberger, P. Immunomodulatory functions of neuronal guidance proteins. Trends Immunol. 38, 444–456 (2017).

    CAS  PubMed  Article  Google Scholar 

  98. 98.

    Wu, J. Y. et al. The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature 410, 948–952 (2001).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  99. 99.

    Tole, S. et al. The axonal repellent, Slit2, inhibits directional migration of circulating neutrophils. J. Leukoc. Biol. 86, 1403–1415 (2009).

    CAS  PubMed  Article  Google Scholar 

  100. 100.

    Pilling, D., Chinea, L. E., Consalvo, K. M. & Gomer, R. H. Different isoforms of the neuronal guidance molecule Slit2 directly cause chemoattraction or chemorepulsion of human neutrophils. J. Immunol. 202, 239–248 (2019).

    CAS  PubMed  Article  Google Scholar 

  101. 101.

    Huttenlocher, A. & Horwitz, A. R. Integrins in cell migration. Cold Spring Harb. Perspect Biol. 3, a005074 (2011).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  102. 102.

    Henning Stumpf, B., Ambriovic´-Ristov, A., Radenovic, A. & Smith, A. S. Recent advances and prospects in the research of nascent adhesions. Front. Physiol. 11, 574371 (2020).

    PubMed  PubMed Central  Article  Google Scholar 

  103. 103.

    Schwarz, J. et al. Dendritic cells interpret haptotactic chemokine gradients in a manner governed by signal-to-noise ratio and dependent on GRK6. Curr Biol 27, 1314–1325 (2017). This study shows differential regulation of the same chemokine receptor in the context of a chemotactic and haptotactic cue.

    CAS  PubMed  Article  Google Scholar 

  104. 104.

    Shellard, A. & Mayor, R. Durotaxis: the hard path from in vitro to in vivo. Dev. Cell https://doi.org/10.1016/j.devcel.2020.11.019 (2020).

    Article  PubMed  Google Scholar 

  105. 105.

    Sunyer, R. & Trepat, X. Durotaxis. Curr. Biol. 30, R383–r387 (2020).

    CAS  PubMed  Article  Google Scholar 

  106. 106.

    Janmey, P. A., Fletcher, D. A. & Reinhart-King, C. A. Stiffness sensing by cells. Physiol. Rev. 100, 695–724 (2020).

    PubMed  Article  Google Scholar 

  107. 107.

    Astrof, N. S., Salas, A., Shimaoka, M., Chen, J. & Springer, T. A. Importance of force linkage in mechanochemistry of adhesion receptors. Biochemistry 45, 15020–15028 (2006).

    CAS  PubMed  Article  Google Scholar 

  108. 108.

    Jiang, G., Huang, A. H., Cai, Y., Tanase, M. & Sheetz, M. P. Rigidity sensing at the leading edge through alphavbeta3 integrins and RPTPalpha. Biophys. J. 90, 1804–1809 (2006).

    CAS  PubMed  Article  Google Scholar 

  109. 109.

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

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  110. 110.

    Moore, T. I., Aaron, J., Chew, T. L. & Springer, T. A. Measuring integrin conformational change on the cell surface with super-resolution microscopy. Cell Rep. 22, 1903–1912 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  111. 111.

    Lämmermann, T. et al. Rapid leukocyte migration by integrin-independent flowing and squeezing. Nature 453, 51–55 (2008).

    PubMed  Article  CAS  Google Scholar 

  112. 112.

    Hetmanski, J. H. R. et al. Membrane tension orchestrates rear retraction in matrix-directed cell migration. Dev. Cell 51, 460–475.e410 (2019). This recent study shows the importance of membrane tension in directed migration.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  113. 113.

    Sitarska, E. & Diz-Muñoz, A. Pay attention to membrane tension: mechanobiology of the cell surface. Curr. Opin. Cell Biol. 66, 11–18 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  114. 114.

    Baschieri, F. et al. Frustrated endocytosis controls contractility-independent mechanotransduction at clathrin-coated structures. Nat. Commun. 9, 3825 (2018).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  115. 115.

    Douguet, D. & Honoré, E. Mammalian mechanoelectrical transduction: structure and function of force-gated ion channels. Cell 179, 340–354 (2019).

    CAS  PubMed  Article  Google Scholar 

  116. 116.

    Goult, B. T., Yan, J. & Schwartz, M. A. Talin as a mechanosensitive signaling hub. J. Cell Biol. 217, 3776–3784 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  117. 117.

    Grashoff, C. et al. Measuring mechanical tension across vinculin reveals regulation of focal adhesion dynamics. Nature 466, 263–266 (2010). This seminal article establishes a tension-based Förster resonance energy transfer biosensor using the focal adhesion protein vinculin.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  118. 118.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  119. 119.

    MacKay, J. L. & Hammer, D. A. Stiff substrates enhance monocytic cell capture through E-selectin but not P-selectin. Integr. Biol. 8, 62–72 (2016).

    CAS  Article  Google Scholar 

  120. 120.

    Sun, X. et al. Mechanosensing through direct binding of tensed F-Actin by LIM domains. Dev. Cell 55, 468–482.e467 (2020).

    CAS  PubMed  Article  Google Scholar 

  121. 121.

    Winkelman, J. D., Anderson, C. A., Suarez, C., Kovar, D. R. & Gardel, M. L. Evolutionarily diverse LIM domain-containing proteins bind stressed actin filaments through a conserved mechanism. Proc. Natl Acad. Sci. USA 117, 25532–25542 (2020). This article, along with Sun et al. (2020), shows that LIM domain-containing proteins bind differentially to actin filaments based on filament tension.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  122. 122.

    Rong, Y. et al. The Golgi microtubules regulate single cell durotaxis. EMBO Rep. https://doi.org/10.15252/embr.202051094 (2021).

    Article  PubMed  Google Scholar 

  123. 123.

    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  Article  Google Scholar 

  124. 124.

    Arsenovic, P. T. et al. Nesprin-2G, a component of the nuclear LINC complex, is subject to myosin-dependent tension. Biophys. J. 110, 34–43 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  125. 125.

    Gomes, E. R., Jani, S. & Gundersen, G. G. Nuclear movement regulated by Cdc42, MRCK, myosin, and actin flow establishes MTOC polarization in migrating cells. Cell 121, 451–463 (2005).

    CAS  PubMed  Article  Google Scholar 

  126. 126.

    Petrie, R. J., Koo, H. & Yamada, K. M. Generation of compartmentalized pressure by a nuclear piston governs cell motility in a 3D matrix. Science 345, 1062–1065 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  127. 127.

    Lou, H. Y., Zhao, W., Zeng, Y. & Cui, B. The role of membrane curvature in nanoscale topography-induced intracellular signaling. Acc. Chem. Res. 51, 1046–1053 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  128. 128.

    Driscoll, M. K., Sun, X., Guven, C., Fourkas, J. T. & Losert, W. Cellular contact guidance through dynamic sensing of nanotopography. ACS Nano 8, 3546–3555 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  129. 129.

    Chen, S. et al. Actin cytoskeleton and focal adhesions regulate the biased migration of breast cancer cells on nanoscale asymmetric sawteeth. ACS Nano 13, 1454–1468 (2019). This article shows that breast cancer cell lines exhibit different migration phenotypes on asymmetric sawtooth nanopatterns through the distinct regulation of actin polymerization waves and focal adhesion dynamics.

    CAS  PubMed  PubMed Central  Google Scholar 

  130. 130.

    Le Maout, E., Lo Vecchio, S., Kumar Korla, P., Jinn-Chyuan Sheu, J. & Riveline, D. Ratchetaxis in channels: entry point and local asymmetry set cell directions in confinement. Biophys. J. 119, 1301–1308 (2020). This article shows how cell direction through 3D ratchet channels is dictated by spatial asymmetry in two-sided confined channels and the entry point of the all-sided confined channels.

    PubMed  Article  CAS  Google Scholar 

  131. 131.

    Ramirez-San Juan, G. R., Oakes, P. W. & Gardel, M. L. Contact guidance requires spatial control of leading-edge protrusion. Mol. Biol. Cell 28, 1043–1053 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  132. 132.

    Jang, K. J. et al. Two distinct filopodia populations at the growth cone allow to sense nanotopographical extracellular matrix cues to guide neurite outgrowth. PLoS ONE 5, e15966 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  133. 133.

    Kubow, K. E., Shuklis, V. D., Sales, D. J. & Horwitz, A. R. Contact guidance persists under myosin inhibition due to the local alignment of adhesions and individual protrusions. Sci. Rep. 7, 14380 (2017). This is a key article showing that cells can sense the topology of aligned fibres even in the absence of myosin activity.

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  134. 134.

    Lou, H. Y. et al. Membrane curvature underlies actin reorganization in response to nanoscale surface topography. Proc. Natl Acad. Sci. USA 116, 23143–23151 (2019). This is an important article identifying membrane curvature-sensing BAR-family protein FBP17 as the bridge between surface topology and topology-induced reorganization of the actin network.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  135. 135.

    McGregor, A. L., Hsia, C. R. & Lammerding, J. Squish and squeeze-the nucleus as a physical barrier during migration in confined environments. Curr. Opin. Cell Biol. 40, 32–40 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  136. 136.

    Lomakin, A. J. et al. The nucleus acts as a ruler tailoring cell responses to spatial constraints. Science https://doi.org/10.1126/science.aba2894 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  137. 137.

    Venturini, V. et al. The nucleus measures shape changes for cellular proprioception to control dynamic cell behavior. Science https://doi.org/10.1126/science.aba2644 (2020). This article, along with Lomakin et al. (2020), shows that cells interpret cell shape and control movement in confined spaces by gauging nuclear deformation and initiating signalling events at the nucleus.

    Article  PubMed  Google Scholar 

  138. 138.

    Zhao, M. Electrical fields in wound healing — an overriding signal that directs cell migration. Semin. Cell Dev. Biol. 20, 674–682 (2009).

    CAS  PubMed  Article  Google Scholar 

  139. 139.

    Allen, G. M., Mogilner, A. & Theriot, J. A. Electrophoresis of cellular membrane components creates the directional cue guiding keratocyte galvanotaxis. Curr. Biol. 23, 560–568 (2013). This is a key article establishing the mechanism of galvanotaxis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  140. 140.

    Sarkar, A., Kobylkevich, B. M., Graham, D. M. & Messerli, M. A. Electromigration of cell surface macromolecules in DC electric fields during cell polarization and galvanotaxis. J. Theor. Biol. 478, 58–73 (2019).

    CAS  PubMed  Article  Google Scholar 

  141. 141.

    Lin, B. J. et al. Lipid rafts sense and direct electric field-induced migration. Proc. Natl Acad. Sci. USA 114, 8568–8573 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  142. 142.

    Li, X., Miao, Y., Pal, D. S. & Devreotes, P. N. Excitable networks controlling cell migration during development and disease. Semin. Cell. Dev. Biol. 100, 133–142 (2020).

    CAS  PubMed  Article  Google Scholar 

  143. 143.

    Xiao, Z., Zhang, N., Murphy, D. B. & Devreotes, P. N. Dynamic distribution of chemoattractant receptors in living cells during chemotaxis and persistent stimulation. J. Cell Biol. 139, 365–374 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  144. 144.

    Servant, G., Weiner, O. D., Neptune, E. R., Sedat, J. W. & Bourne, H. R. Dynamics of a chemoattractant receptor in living neutrophils during chemotaxis. Mol. Biol. Cell 10, 1163–1178 (1999).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  145. 145.

    Nieto, M. et al. Polarization of chemokine receptors to the leading edge during lymphocyte chemotaxis. J. Exp. Med. 186, 153–158 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  146. 146.

    Bailly, M. et al. Epidermal growth factor receptor distribution during chemotactic responses. Mol. Biol. Cell 11, 3873–3883 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  147. 147.

    Bergeron, J. J., Di Guglielmo, G. M., Dahan, S., Dominguez, M. & Posner, B. I. Spatial and temporal regulation of receptor tyrosine kinase activation and intracellular signal transduction. Annu. Rev. Biochem. 85, 573–597 (2016).

    CAS  PubMed  Article  Google Scholar 

  148. 148.

    Callan-Jones, A. C. & Voituriez, R. Actin flows in cell migration: from locomotion and polarity to trajectories. Curr. Opin. Cell Biol. 38, 12–17 (2016).

    CAS  PubMed  Article  Google Scholar 

  149. 149.

    Parent, C. A., Blacklock, B. J., Froehlich, W. M., Murphy, D. B. & Devreotes, P. N. G protein signaling events are activated at the leading edge of chemotactic cells. Cell 95, 81–91 (1998).

    CAS  PubMed  Article  Google Scholar 

  150. 150.

    Servant, G. et al. Polarization of chemoattractant receptor signaling during neutrophil chemotaxis. Science 287, 1037–1040 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  151. 151.

    Haugh, J. M., Codazzi, F., Teruel, M. & Meyer, T. Spatial sensing in fibroblasts mediated by 3’ phosphoinositides. J. Cell Biol. 151, 1269–1280 (2000).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  152. 152.

    Artemenko, Y., Lampert, T. J. & Devreotes, P. N. Moving towards a paradigm: common mechanisms of chemotactic signaling in Dictyostelium and mammalian leukocytes. Cell Mol. Life Sci. 71, 3711–3747 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  153. 153.

    Kunisaki, Y. et al. DOCK2 is a Rac activator that regulates motility and polarity during neutrophil chemotaxis. J. Cell Biol. 174, 647–652 (2006).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  154. 154.

    Zhao, T. et al. Signaling requirements for translocation of P-Rex1, a key Rac2 exchange factor involved in chemoattractant-stimulated human neutrophil function. J. Leukoc. Biol. 81, 1127–1136 (2007).

    CAS  PubMed  Article  Google Scholar 

  155. 155.

    Yan, J. et al. A Gβγ effector, ElmoE, transduces GPCR signaling to the actin network during chemotaxis. Dev. Cell 22, 92–103 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  156. 156.

    Asokan, S. B. et al. Mesenchymal chemotaxis requires selective inactivation of myosin II at the leading edge via a noncanonical PLCgamma/PKCalpha pathway. Dev. Cell 31, 747–760 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  157. 157.

    Hoeller, O. & Kay, R. R. Chemotaxis in the absence of PIP3 gradients. CB 17, 813–817 (2007).

    CAS  PubMed  Google Scholar 

  158. 158.

    Liu, L., Das, S., Losert, W. & Parent, C. A. mTORC2 regulates neutrophil chemotaxis in a cAMP- and RhoA-dependent fashion. Dev. Cell 19, 845–857 (2010).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  159. 159.

    Chen, M. Y., Long, Y. & Devreotes, P. N. A novel cytosolic regulator, Pianissimo, is required for chemoattractant receptor and G protein-mediated activation of the 12 transmembrane domain adenylyl cyclase in Dictyostelium. Genes Dev. 11, 3218–3231 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  160. 160.

    Lee, S. et al. TOR complex 2 integrates cell movement during chemotaxis and signal relay in Dictyostelium. Mol. Biol. Cell 16, 4572–4583 (2005).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  161. 161.

    He, Y. et al. Mammalian target of rapamycin and Rictor control neutrophil chemotaxis by regulating Rac/Cdc42 activity and the actin cytoskeleton. Mol. Biol. Cell 24, 3369–3380 (2013).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  162. 162.

    Chen, L. et al. PLA2 and PI3K/PTEN pathways act in parallel to mediate chemotaxis. Dev. Cell 12, 603–614 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  163. 163.

    van Haastert, P. J., Keizer-Gunnink, I. & Kortholt, A. Essential role of PI3-kinase and phospholipase A2 in Dictyostelium discoideum chemotaxis. J. Cell Biol. 177, 809–816 (2007).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  164. 164.

    Heit, B. et al. PTEN functions to ‘prioritize’ chemotactic cues and prevent ‘distraction’ in migrating neutrophils. Nat. Immunol. 9, 743–752 (2008).

    CAS  PubMed  Article  Google Scholar 

  165. 165.

    Meliton, A. Y. et al. Cytosolic group IVa phospholipase A2 mediates IL-8/CXCL8-induced transmigration of human polymorphonuclear leukocytes in vitro. J. Inflamm. 7, 14 (2010).

    Article  CAS  Google Scholar 

  166. 166.

    Yonker, L. M. et al. Neutrophil-derived cytosolic PLA2α contributes to bacterial-induced neutrophil transepithelial migration. J. Immunol. 199, 2873–2884 (2017).

    CAS  PubMed  Article  Google Scholar 

  167. 167.

    Ma, H., Gamper, M., Parent, C. & Firtel, R. A. The Dictyostelium MAP kinase kinase DdMEK1 regulates chemotaxis and is essential for chemoattractant-mediated activation of guanylyl cyclase. EMBO J. 16, 4317–4332 (1997).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  168. 168.

    Mendoza, M. C., Booth, E. O., Shaulsky, G. & Firtel, R. A. MEK1 and protein phosphatase 4 coordinate Dictyostelium development and chemotaxis. Mol. Cell Biol. 27, 3817–3827 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  169. 169.

    Heit, B., Tavener, S., Raharjo, E. & Kubes, P. An intracellular signaling hierarchy determines direction of migration in opposing chemotactic gradients. J. Cell Biol. 159, 91–102 (2002).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  170. 170.

    Liu, X. et al. Bidirectional regulation of neutrophil migration by mitogen-activated protein kinases. Nat. Immunol. 13, 457–464 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  171. 171.

    Mouneimne, G. et al. Spatial and temporal control of cofilin activity is required for directional sensing during chemotaxis. Curr. Biol. 16, 2193–2205 (2006).

    CAS  PubMed  Article  Google Scholar 

  172. 172.

    Miao, Y. et al. Altering the threshold of an excitable signal transduction network changes cell migratory modes. Nat. Cell Biol. 19, 329–340 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  173. 173.

    Zhan, H. et al. An excitable Ras/PI3K/ERK signaling network controls migration and oncogenic transformation in epithelial cells. Dev. Cell 54, 608–623.e605 (2020).

    PubMed  Article  CAS  Google Scholar 

  174. 174.

    King, S. J. et al. Lamellipodia are crucial for haptotactic sensing and response. J. Cell Sci. 129, 2329–2342 (2016).

    CAS  PubMed  PubMed Central  Google Scholar 

  175. 175.

    Cox, C. D., Bavi, N. & Martinac, B. Biophysical principles of ion-channel-mediated mechanosensory transduction. Cell Rep. 29, 1–12 (2019).

    CAS  PubMed  Article  Google Scholar 

  176. 176.

    Pal, N., Wu, M. & Lu, H. P. Probing conformational dynamics of an enzymatic active site by an in situ single fluorogenic probe under piconewton force manipulation. Proc. Natl Acad. Sci. USA 113, 15006–15011 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  177. 177.

    Hu, X., Margadant, F. M., Yao, M. & Sheetz, M. P. Molecular stretching modulates mechanosensing pathways. Protein Sci. 26, 1337–1351 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  178. 178.

    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  Article  Google Scholar 

  179. 179.

    Rothenberg, K. E., Scott, D. W., Christoforou, N. & Hoffman, B. D. Vinculin force-sensitive dynamics at focal adhesions enable effective directed cell migration. Biophys. J. 114, 1680–1694 (2018). This recent work using the vinculin Förster resonance energy transfer-based tension sensor shows precise regulation of tension at different focal adhesions during directed migration.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  180. 180.

    Ringer, P. et al. Multiplexing molecular tension sensors reveals piconewton force gradient across talin-1. Nat Methods 14, 1090–1096 (2017).

    CAS  PubMed  Article  Google Scholar 

  181. 181.

    LaCroix, A. S., Lynch, A. D., Berginski, M. E. & Hoffman, B. D. Tunable molecular tension sensors reveal extension-based control of vinculin loading. eLife https://doi.org/10.7554/eLife.33927 (2018).

    Article  PubMed  PubMed Central  Google Scholar 

  182. 182.

    Huang, D. L., Bax, N. A., Buckley, C. D., Weis, W. I. & Dunn, A. R. Vinculin forms a directionally asymmetric catch bond with F-actin. Science 357, 703–706 (2017).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  183. 183.

    Owen, L. M., Bax, N. A., Weis, W. I. & Dunn, A. R. The C-terminal actin binding domain of talin forms an asymmetric catch bond with F-actin. Preprint at bioRxiv https://doi.org/10.1101/2020.09.01.276568 (2020).

    Article  PubMed  PubMed Central  Google Scholar 

  184. 184.

    Singh, A. V. et al. Astrocytes increase ATP exocytosis mediated calcium signaling in response to microgroove structures. Sci. Rep. 5, 7847 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  185. 185.

    Hung, W. C. et al. Confinement sensing and signal optimization via Piezo1/PKA and myosin II pathways. Cell Rep. 15, 1430–1441 (2016).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  186. 186.

    Bavi, N., Richardson, J., Heu, C., Martinac, B. & Poole, K. PIEZO1-mediated currents are modulated by substrate mechanics. ACS Nano 13, 13545–13559 (2019). This article shows that the surface geometry, including roughness and stiffness, modulates PIEZO1 channel activation in response to the external mechanical force applied at cell–substrate interfaces.

    CAS  PubMed  Article  Google Scholar 

  187. 187.

    Subramanian, B. C. et al. The LTB4-BLT1 axis regulates actomyosin and β2-integrin dynamics during neutrophil extravasation. J. Cell Biol. https://doi.org/10.1083/jcb.201910215 (2020). This article reports a critical role for neutrophil-derived LTB4 in the regulation of non-muscle myosin II and β2 integrin that depends on the release of extracellular vesicles during neutrophil arrest and extravasation in live mice.

    Article  PubMed  PubMed Central  Google Scholar 

  188. 188.

    Gao, R. et al. A large-scale screen reveals genes that mediate electrotaxis in Dictyostelium discoideum. Sci. Signal 8, ra50 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  189. 189.

    Sánchez, M. F., Els-Heindl, S., Beck-Sickinger, A. G., Wieneke, R. & Tampé, R. Photo-induced receptor confinement drives ligand-independent GPCR signaling. Science https://doi.org/10.1126/science.abb7657 (2021).

    Article  PubMed  Google Scholar 

  190. 190.

    Smith, H. E. Nematode sperm motility. WormBook https://doi.org/10.1895/wormbook.1.68.2 (2014).

    Article  PubMed  PubMed Central  Google Scholar 

  191. 191.

    Pollard, T. D. & Borisy, G. G. Cellular motility driven by assembly and disassembly of actin filaments. Cell 112, 453–465 (2003).

    CAS  PubMed  Article  Google Scholar 

  192. 192.

    Bodor, D. L., Pönisch, W., Endres, R. G. & Paluch, E. K. Of cell shapes and motion: the physical basis of animal cell migration. Dev. Cell 52, 550–562 (2020).

    CAS  PubMed  Article  Google Scholar 

  193. 193.

    Krause, M. & Gautreau, A. Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat. Rev. Mol. Cell Biol. 15, 577–590 (2014).

    CAS  PubMed  Article  Google Scholar 

  194. 194.

    McCormick, L. E. & Gupton, S. L. Mechanistic advances in axon pathfinding. Curr. Opin. Cell Biol. 63, 11–19 (2020).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  195. 195.

    Johnson, H. E. et al. F-actin bundles direct the initiation and orientation of lamellipodia through adhesion-based signaling. J. Cell Biol. 208, 443–455 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  196. 196.

    Svitkina, T. M. et al. Mechanism of filopodia initiation by reorganization of a dendritic network. J. Cell Biol. 160, 409–421 (2003).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  197. 197.

    Wu, C. et al. Arp2/3 is critical for lamellipodia and response to extracellular matrix cues but is dispensable for chemotaxis. Cell 148, 973–987 (2012). This is the first article to establish that the Arp2/3 complex is required for ECM haptotaxis but is dispensable for RTK-dependent chemotaxis in fibroblasts.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  198. 198.

    Schaks, M., Giannone, G. & Rottner, K. Actin dynamics in cell migration. Essays Biochem. 63, 483–495 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  199. 199.

    Collins, S. R. et al. Using light to shape chemical gradients for parallel and automated analysis of chemotaxis. Mol. Syst. Biol. 11, 804 (2015).

    PubMed  PubMed Central  Article  CAS  Google Scholar 

  200. 200.

    Davidson, A. J., Amato, C., Thomason, P. A. & Insall, R. H. WASP family proteins and formins compete in pseudopod- and bleb-based migration. J. Cell Biol. 217, 701–714 (2018).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  201. 201.

    Vargas, P. et al. Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells. Nat. Cell Biol. 18, 43–53 (2016).

    CAS  PubMed  Article  Google Scholar 

  202. 202.

    Menon, S. et al. The E3 ubiquitin ligase TRIM9 is a filopodia off switch required for netrin-dependent axon guidance. Dev. Cell 35, 698–712 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  203. 203.

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

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  204. 204.

    Wong, S., Guo, W. H. & Wang, Y. L. Fibroblasts probe substrate rigidity with filopodia extensions before occupying an area. Proc. Natl Acad. Sci. USA 111, 17176–17181 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  205. 205.

    Andrew, N. & Insall, R. H. Chemotaxis in shallow gradients is mediated independently of PtdIns 3-kinase by biased choices between random protrusions. Nat. Cell Biol. 9, 193–200 (2007).

    CAS  PubMed  Article  Google Scholar 

  206. 206.

    Welf, E. S., Ahmed, S., Johnson, H. E., Melvin, A. T. & Haugh, J. M. Migrating fibroblasts reorient directionality by a metastable, PI3K-dependent mechanism. J. Cell Biol. 197, 105–114 (2012).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  207. 207.

    Sun, X. et al. Asymmetric nanotopography biases cytoskeletal dynamics and promotes unidirectional cell guidance. Proc. Natl Acad. Sci. USA 112, 12557–12562 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  208. 208.

    Vicente-Manzanares, M., Ma, X., Adelstein, R. S. & Horwitz, A. R. Non-muscle myosin II takes centre stage in cell adhesion and migration. Nat. Rev. Mol. Cell Biol. 10, 778–790 (2009).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  209. 209.

    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  Article  Google Scholar 

  210. 210.

    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).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  211. 211.

    Mayor, R. & Etienne-Manneville, S. The front and rear of collective cell migration. Nat. Rev. Mol. Cell Biol. 17, 97–109 (2016).

    CAS  PubMed  Article  Google Scholar 

  212. 212.

    Ladoux, B. & Mège, R. M. Mechanobiology of collective cell behaviours. Nat. Rev. Mol. Cell Biol. 18, 743–757 (2017).

    CAS  PubMed  Article  Google Scholar 

  213. 213.

    Shellard, A., Szabó, A., Trepat, X. & Mayor, R. Supracellular contraction at the rear of neural crest cell groups drives collective chemotaxis. Science 362, 339–343 (2018). This article shows a rear wheel drive-like motility during collective chemotaxis by actomyosin contractility in a cluster of rear cells.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  214. 214.

    Yam, P. T. et al. Actin-myosin network reorganization breaks symmetry at the cell rear to spontaneously initiate polarized cell motility. J. Cell Biol. 178, 1207–1221 (2007).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  215. 215.

    Tsai, T. Y. et al. Efficient front-rear coupling in neutrophil chemotaxis by dynamic myosin II localization. Dev. Cell 49, 189–205.e186 (2019). This article shows that the side-to-side redistribution of myosin II at the back of cells in response to leading-edge turning is critical for maintaining persistence and turning ability in neutrophils undergoing chemotaxis.

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  216. 216.

    Allen, G. M. et al. Cell mechanics at the rear act to steer the direction of cell migration. Cell Syst. 11, 286–299.e284 (2020).

    CAS  PubMed  Article  Google Scholar 

  217. 217.

    Charras, G. & Paluch, E. Blebs lead the way: how to migrate without lamellipodia. Nat. Rev. Mol. Cell Biol. 9, 730–736 (2008).

    CAS  PubMed  Article  Google Scholar 

  218. 218.

    Zatulovskiy, E., Tyson, R., Bretschneider, T. & Kay, R. R. Bleb-driven chemotaxis of Dictyostelium cells. J. Cell Biol. 204, 1027–1044 (2014).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  219. 219.

    Reversat, A. et al. Cellular locomotion using environmental topography. Nature 582, 582–585 (2020). This article identifies friction force generated by retrograde flow of actin propelling cells forward through a 3D environment in the absence of integrin engagement.

    CAS  PubMed  Article  Google Scholar 

  220. 220.

    Aoun, L. et al. Amoeboid swimming is propelled by molecular paddling in lymphocytes. Biophys. J. 119, 1157–1177 (2020). This fascinating recent work demonstrates a new mechanism of cell swimming using ‘molecular paddling’ of cell surface proteins coupled to flow of the underlying cell cortex.

    PubMed  Article  CAS  Google Scholar 

  221. 221.

    Purcell, E. M. Life at low Reynolds number. Am. J. Phys. 45, 3–11 (1977).

    Article  Google Scholar 

  222. 222.

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

    CAS  PubMed  Article  Google Scholar 

  223. 223.

    Dai, W. et al. Tissue topography steers migrating Drosophila border cells. Science 370, 987–990 (2020). This article shows that while chemical cues promote posterior movement, topographical cues provide orthogonal information and a path of least resistance during the migration of border cells in the egg chamber of D. melanogaster embryos.

    CAS  PubMed  Article  Google Scholar 

  224. 224.

    Mathias, J. R. et al. Resolution of inflammation by retrograde chemotaxis of neutrophils in transgenic zebrafish. J. Leukoc. Biol. 80, 1281–1288 (2006).

    CAS  PubMed  Article  Google Scholar 

  225. 225.

    Wang, J. et al. Visualizing the function and fate of neutrophils in sterile injury and repair. Science 358, 111–116 (2017).

    CAS  PubMed  Article  Google Scholar 

  226. 226.

    Hind, L. E. & Huttenlocher, A. Neutrophil reverse migration and a chemokinetic resolution. Dev. Cell 47, 404–405 (2018).

    CAS  PubMed  Article  Google Scholar 

  227. 227.

    Paluch, E. K., Aspalter, I. M. & Sixt, M. Focal adhesion-independent cell migration. Annu. Rev. Cell Dev. Biol. 32, 469–490 (2016).

    CAS  PubMed  Article  Google Scholar 

  228. 228.

    Shellard, A. & Mayor, R. All roads lead to directional cell migration. Trends Cell Biol. 30, 852–868 (2020).

    CAS  PubMed  Article  Google Scholar 

  229. 229.

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

    PubMed  Article  Google Scholar 

  230. 230.

    Lämmermann, T. & Sixt, M. Mechanical modes of ‘amoeboid’ cell migration. Curr. Opin. Cell Biol. 21, 636–644 (2009).

    PubMed  Article  CAS  Google Scholar 

  231. 231.

    Pagès, D.-L. et al. Cell clusters adopt a collective amoeboid mode of migration in confined non-adhesive environments. Preprint at bioRxiv https://doi.org/10.1101/2020.05.28.106203 (2020).

    Article  Google Scholar 

  232. 232.

    Liu, Y. J. et al. Confinement and low adhesion induce fast amoeboid migration of slow mesenchymal cells. Cell 160, 659–672 (2015).

    CAS  PubMed  Article  Google Scholar 

  233. 233.

    Ruprecht, V. et al. Cortical contractility triggers a stochastic switch to fast amoeboid cell motility. Cell 160, 673–685 (2015).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  234. 234.

    Graziano, B. R. et al. Cell confinement reveals a branched-actin independent circuit for neutrophil polarity. PLoS Biol. 17, e3000457 (2019).

    CAS  PubMed  PubMed Central  Article  Google Scholar 

  235. 235.

    Lehmann, S. et al. Hypoxia induces a HIF-1-dependent transition from collective-to-amoeboid dissemination in epithelial cancer cells. Curr. Biol. 27, 392–400 (2017).

    CAS  PubMed  Article  Google Scholar 

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Acknowledgements

The authors apologize to their colleagues whose work on this vast topic they were unable to cite due to length constraints. They thank M. Butler for designing some of the artwork in Fig. 3c, and J. Haugh for thoughtful discussions. J.E.B. acknowledges support from the NIH (R35GM130312 and U01EB018816). C.A.P. acknowledges support from the NIH (R01AI152517).

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Correspondence to James E. Bear.

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Glossary

Lamellipodia

Broad, sheet-like protrusions that contain branched and linear actin filaments. A variety of cell types, including fibroblasts, neural crest cells and macrophages, use lamellipodia to explore longer distances through the extracellular matrix.

Filopodia

Finger-like protrusions that contain bundles of linear F-actin. Filopodia serve to probe local environmental cues, provide directionality and maintain persistence of migrating cells.

Stress fibres

Contractile arrays of actin and non-muscle myosin II that are mechanically coupled to the substrate through integrin-based focal adhesions.

Substrate compliance

The mechanical resistance provided by non-rigid substrates (for example, collagen gels) to the contractile forces exerted by cells as they engage the substrate.

Complement

Complement proteins are products of the complement pathway generally activated as part of the innate immune response to infection. Some complement proteins, such as C5a, act as chemoattractants that guide leukocytes to sites of infection.

Posterior lateral line primordium

A group of cells that migrate together from the ear to the tip of the tail of zebrafish as they periodically deposit primary neuromasts.

Morphogens

Signal molecules that originate from a tissue and diffuse to generate a concentration gradient. Morphogens exert long-range signalling effects important for growth and tissue patterning during development.

Advection fields

Fluid flows such as interstitial flow in tissues that can create an advection field or directional transfer of molecules in the liquid phase around cells, which in turn can create asymmetries in secreted autocrine chemoattractants, leading to autologous chemotaxis. Advection fields can also form in the cytoplasm.

Extracellular vesicles

A group of heterogeneous vesicles (several nanometres to micrometres in size) that carry a variety of cargos, including proteins, lipids and nucleic acids, and are secreted by cells to the extracellular space to facilitate cell–cell communication.

Exosomes

The smallest subtype of extracellular vesicles, with a size ranging from 50 to 150 nm. Exosomes are generated as intraluminal vesicles which are secreted to the extracellular space when intraluminal vesicle-carrying multivesicular bodies fuse with the plasma membrane.

Caveolin

Integral membrane protein family required for flask-shaped (caveola) membrane structure formation. Caveolins are also involved in membrane trafficking, exocytosis, endocytosis, extracellular vesicle formation and extracellular vesicle cargo selection.

Rho-family GTPases

A family of small proteins that bind GDP or GTP and regulate a wide array of downstream signalling events. CDC42, Rac, and RhoA are widely studied members of this family of proteins.

G protein-coupled receptors

(GPCRs). A family of plasma membrane receptors composed of seven transmembrane domains that couple to heterotrimeric G proteins to regulate responses mediated by a variety of external signals.

Axon growth cone

Motile structure at the tip of growing axons that guides directed extension of the axon and is important for patterning of the nervous system.

Cell–cell junctions

Stable or dynamic sites where borders of two neighbouring cells contact each other. Cell–cell adhesion receptors and recruited adaptor proteins are mechanically coupled to the actin cytoskeleton.

Focal adhesions

Multiprotein assemblies that physically connect extracellular matrix components to the intracellular actin cytoskeleton through integrin clusters. Integrin-mediated adhesion to extracellular matrix ligands recruits a plethora of signalling (Src and FAK) and structural (talin, paxillin and vinculin) molecules to focal adhesions. Large, mechanically engaged focal adhesions play a crucial role in sensing mechanical cues, while smaller, nascent adhesions are critical for sensing haptotactic cues.

Traction force

The stress vector at the interface between a migrating cell and its substrate.

LIM domains

Protein structural domains named after the proteins LIN-11, ISL1 and MEC-3. A subset of these domains, such as those found in the proteins zyxin, paxillin and testin, bind actin filaments in a mechanical stress-dependent manner.

LINC complex

Linker of nucleoskeleton and cytoskeleton (LINC) complex is a complex of nuclear envelope proteins that connects the cytoskeleton to the nuclear lamina and is thus involved in transferring signals from sensing mechanical cues at the cell surface or in the cytosol into nucleus.

BAR-family proteins

Bin/amphiphysin/Rvs161 domain (BAR) proteins are membrane-binding proteins that aid in regulating membrane shape.

Arp2/3 complex

A seven-subunit protein complex that possesses actin nucleation and branching activities leading to the generation of branched actin networks.

N-WASP

Neuronal Wiskott–Aldrich syndrome protein activates the Arp2/3 complex and promotes branched actin filament formation.

Cortactin

A nucleation promoting factor that activates the Arp2/3 complex and promotes branched actin filament formation.

Pleckstrin homology (PH) domain

Small protein domains of approximately 120 amino acids that are known to have phosphoinositide-binding specificity.

DOCK–ELMO

A protein complex consisting of an adaptor protein, ELMO, and a Rac-specific guanine nucleotide exchange factor, DOCK.

TORC2

Target of rapamycin complex 2 is composed of seven conserved subunits and is involved in regulating proliferation, survival, cell migration and cytoskeletal reorganization.

Phospholipase A2

An enzyme that cleaves phospholipids to give rise to lipid products (arachidonic acid or lysophosphatidic acid) that either have the ability to regulate signalling events or are substrates in the generation of bioactive lipids.

MAPK/ERK

A group of protein kinases that transduce signals from cell surface receptors to the nucleus.

Förster resonance energy transfer

A mechanism describing energy transfer between two light-sensitive molecules.

Pseudopodia

Protrusive structures in amoeboid cells generated by branched and linear actin filament arrays in the leading edge and aligned with the direction of movement.

Ena/VASP

Enabled/vasodilator-stimulated phosphoproteins are actin polymerases that drive actin filament elongation and antagonize filament capping, leading to the generation of linear actin filaments.

Formin

A group of actin polymerases that drives the formation of linear actin filaments.

SCAR/WAVE

Suppressor of cAR/WASP family verprolin-homologous protein is a nucleation-promoting factor that activates actin nucleation activity of the Arp2/3 complex.

Calpain

Calcium-activated cysteine protease that cleaves adhesion complex proteins.

Border cell

A specialized cell type that migrates as a group through the egg chambers in Drosophila melanogaster.

Blebs

Spherical membrane protrusions that rely on myosin-based contraction and pressure-driven cytosolic flow. Bleb-like protrusions are commonly used for motility by amoebas and embryonic cells. However, leukocytes and tumour cells can use blebbing motility especially in 3D environments under confined conditions.

Reynolds number

A dimensionless number important in fluid mechanics. Cellular scales are inherently a low Reynolds number environment where inertia and momentum are negligible and thus movement requires strategies different from those for human-relevant length scales.

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SenGupta, S., Parent, C.A. & Bear, J.E. The principles of directed cell migration. Nat Rev Mol Cell Biol 22, 529–547 (2021). https://doi.org/10.1038/s41580-021-00366-6

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