To reach their destination, migrating cells rely on polarized signal inputs to align the direction of their motion. However, navigational guidance cues are not always present, which establishes the need for exploratory search mechanisms in cells seeking signal inputs. Here, we investigate how non-Brownian search patterns emerge in adherent vertebrate cells. Combining experimental and theoretical analysis, we demonstrate that nanoscale plasma membrane deformations nucleate a mechanochemical feedback loop that mediates longevity of the cell’s leading edge, a necessary requirement for directed cell migration. We further observe stochastic transitions between phases of random and persistent cell motion, whereby the mechanochemical circuit augments cell persistence and search area. Collectively, these findings are consistent with a self-organizing system for a superdiffusive pattern of motion that is spontaneously employed by migratory cells in the absence of external signal inputs.
Access optionsAccess options
Subscribe to Journal
Get full journal access for 1 year
only $15.58 per issue
All prices are NET prices.
VAT will be added later in the checkout.
Rent or Buy article
Get time limited or full article access on ReadCube.
All prices are NET prices.
The data that support the findings of this study are available from the corresponding author on reasonable request. No restrictions apply.
Publisher’s note: Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Bourne, H. R. & Weiner, O. A chemical compass. Nature 419, 21 (2002).
Iglesias, P. A. & Devreotes, P. N. Biased excitable networks: how cells direct motion in response to gradients. Curr. Opin. Cell Biol. 24, 245–253 (2012).
Harris, T. H. et al. Generalized Levy walks and the role of chemokines in migration of effector CD8+ T cells. Nature 486, 545–548 (2012).
Vargas, P. et al. Innate control of actin nucleation determines two distinct migration behaviours in dendritic cells. Nat. Cell Biol. 18, 43–53 (2016).
Viswanathan, G. M. et al. Optimizing the success of random searches. Nature 401, 911–914 (1999).
Benichou, O., Coppey, M., Moreau, M., Suet, P. H. & Voituriez, R. Optimal search strategies for hidden targets. Phys. Rev. Lett. 94, 198101 (2005).
Benichou, O., Loverdo, C., Moreau, M. & Voituriez, R. Two-dimensional intermittent search processes: an alternative to Levy flight strategies. Phys. Rev. E 74, 020102 (2006).
Jikeli, J. F. et al. Sperm navigation along helical paths in 3D chemoattractant landscapes. Nat. Commun. 6, 7985 (2015).
Charras, G. & Paluch, E. Blebs lead the way: how to migrate without lamellipodia. Nat. Rev. Mol. Cell Biol. 9, 730–736 (2008).
Small, J. V., Stradal, T., Vignal, E. & Rottner, K. The lamellipodium: where motility begins. Trends Cell Biol. 12, 112–120 (2002).
Maiuri, P. et al. Actin flows mediate a universal coupling between cell speed and cell persistence. Cell 161, 374–386 (2015).
Xu, J. et al. Divergent signals and cytoskeletal assemblies regulate self-organizing polarity in neutrophils. Cell 114, 201–214 (2003).
Gardel, M. L. et al. Traction stress in focal adhesions correlates biphasically with actin retrograde flow speed. J. Cell Biol. 183, 999–1005 (2008).
Beningo, K. A., Dembo, M., Kaverina, I., Small, J. V. & Wang, Y. L. Nascent focal adhesions are responsible for the generation of strong propulsive forces in migrating fibroblasts. J. Cell Biol. 153, 881–888 (2001).
Short, B. Lamellipodial actin branches out. J. Cell Biol. 211, 6 (2015).
Svitkina, T. M., Verkhovsky, A. B., McQuade, K. M. & Borisy, G. G. Analysis of the actin-myosin II system in fish epidermal keratocytes: mechanism of cell body translocation. J. Cell Biol. 139, 397–415 (1997).
Svitkina, T. M. & Borisy, G. G. Arp2/3 complex and actin depolymerizing factor/cofilin in dendritic organization and treadmilling of actin filament array in lamellipodia. J. Cell Biol. 145, 1009–1026 (1999).
Giannone, G. et al. Periodic lamellipodial contractions correlate with rearward actin waves. Cell 116, 431–443 (2004).
Giannone, G. et al. Lamellipodial actin mechanically links myosin activity with adhesion-site formation. Cell 128, 561–575 (2007).
Krause, M. & Gautreau, A. Steering cell migration: lamellipodium dynamics and the regulation of directional persistence. Nat. Rev. Mol. Cell Biol. 15, 577–590 (2014).
Harms, B. D., Bassi, G. M., Horwitz, A. R. & Lauffenburger, D. A. Directional persistence of EGF-induced cell migration is associated with stabilization of lamellipodial protrusions. Biophys. J. 88, 1479–1488 (2005).
Wollman, R. & Meyer, T. Coordinated oscillations in cortical actin and Ca2+ correlate with cycles of vesicle secretion. Nat. Cell Biol. 14, 1261–1269 (2012).
Chen, B. C. et al. Lattice light-sheet microscopy: imaging molecules to embryos at high spatiotemporal resolution. Science 346, 1257998 (2014).
Planchon, T. A. et al. Rapid three-dimensional isotropic imaging of living cells using Bessel beam plane illumination. Nat. Methods 8, 417–423 (2011).
Gov, N. S. & Gopinathan, A. Dynamics of membranes driven by actin polymerization. Biophys. J. 90, 454–469 (2006).
Ramaswamy, S., Toner, J. & Prost, J. Nonequilibrium fluctuations, traveling waves, and instabilities in active membranes. Phys. Rev. Lett. 84, 3494–3497 (2000).
Shlomovitz, R. & Gov, N. S. Membrane waves driven by actin and myosin. Phys. Rev. Lett. 98, 168103 (2007).
Eden, S., Rohatgi, R., Podtelejnikov, A. V., Mann, M. & Kirschner, M. W. Mechanism of regulation of WAVE1-induced actin nucleation by Rac1 and Nck. Nature 418, 790–793 (2002).
Miki, H., Yamaguchi, H., Suetsugu, S. & Takenawa, T. IRSp53 is an essential intermediate between Rac and WAVE in the regulation of membrane ruffling. Nature 408, 732–735 (2000).
Nakagawa, H. et al. IRSp53 is colocalised with WAVE2 at the tips of protruding lamellipodia and filopodia independently of Mena. J. Cell Sci. 116, 2577–2583 (2003).
Prevost, C. et al. IRSp53 senses negative membrane curvature and phase separates along membrane tubules. Nat. Commun. 6, 8529 (2015).
Mattila, P. K. et al. Missing-in-metastasis and IRSp53 deform PI(4,5)P2-rich membranes by an inverse BAR domain-like mechanism. J. Cell Biol. 176, 953–964 (2007).
Yamagishi, A., Masuda, M., Ohki, T., Onishi, H. & Mochizuki, N. A novel actin bundling/filopodium-forming domain conserved in insulin receptor tyrosine kinase substrate p53 and missing in metastasis protein. J. Biol. Chem. 279, 14929–14936 (2004).
Millard, T. H. et al. Structural basis of filopodia formation induced by the IRSp53/MIM homology domain of human IRSp53. EMBO J. 24, 240–250 (2005).
Galic, M. et al. External push and internal pull forces recruit curvature-sensing N-BAR domain proteins to the plasma membrane. Nat. Cell Biol. 14, 874–881 (2012).
Galic, M. et al. Dynamic recruitment of the curvature-sensitive protein ArhGAP44 to nanoscale membrane deformations limits exploratory filopodia initiation in neurons. eLife 3, e03116 (2014).
Begemann, I., Viplav, A., Rasch, C. & Galic, M. Stochastic micro-pattern for automated correlative fluorescence–scanning electron microscopy. Sci. Rep. 5, 17973 (2015).
Brock, A. et al. Geometric determinants of directional cell motility revealed using microcontact printing. Langmuir 19, 1611–1617 (2003).
Suetsugu, S. et al. Optimization of WAVE2 complex-induced actin polymerization by membrane-bound IRSp53, PIP(3), and Rac. J. Cell Biol. 173, 571–585 (2006).
Shutova, M., Yang, C., Vasiliev, J. M. & Svitkina, T. Functions of nonmuscle myosin II in assembly of the cellular contractile system. PloS ONE 7, e40814 (2012).
Roux, A. et al. Membrane curvature controls dynamin polymerization. Proc. Natl Acad. Sci. USA 107, 4141–4146 (2010).
Berg, H. C. & Brown, D. A. Chemotaxis in Escherichia coli analyzed by three-dimensional tracking. Antibiot. Chemother. 19, 55–78 (1974).
Berg, H. C. & Brown, D. A. Chemotaxis in Escherichia coli analysed by three-dimensional tracking. Nature 239, 500–504 (1972).
Huber, A. R., Kunkel, S. L., Todd, R. F. III & Weiss, S. J. Regulation of transendothelial neutrophil migration by endogenous interleukin-8. Science 254, 99–102 (1991).
Kreisel, D. et al. In vivo two-photon imaging reveals monocyte-dependent neutrophil extravasation during pulmonary inflammation. Proc. Natl Acad. Sci. USA 107, 18073–18078 (2010).
Zheng, D. et al. Abba promotes PDGF-mediated membrane ruffling through activation of the small GTPase Rac1. Biochem. Biophys. Res. Commun. 401, 527–532 (2010).
Weiner, O. D. et al. Spatial control of actin polymerization during neutrophil chemotaxis. Nat. Cell Biol. 1, 75–81 (1999).
Zheng, X. et al. Non-Gaussian statistics for the motion of self-propelled Janus particles, experiment versus theory. Phys Rev E 88, 032304 (2013).
Yamada, D., Hondou, T. & Sano, M. Coherent dynamics of an asymmetric particle in a vertically vibrating bed. Phys Rev E 67, 040301 (2003).
Wu, C. et al. BioGPS: an extensible and customizable portal for querying and organizing gene annotation resources. Genome Biol. 10, R130 (2009).
Houk, A. R. et al. Membrane tension maintains cell polarity by confining signals to the leading edge during neutrophil migration. Cell 148, 175–188 (2012).
Meinhardt, H. & Gierer, A. Applications of a theory of biological pattern formation based on lateral inhibition. J. Cell Sci. 15, 321–346 (1974).
Jilkine, A. & Edelstein-Keshet, L. A comparison of mathematical models for polarization of single eukaryotic cells in response to guided cues. PLoS Comput. Biol. 7, e1001121 (2011).
We would like to thank A. Ricker, K. Tkotz, J. Lehrich, A. Bodzeta, H. Nüsse and S. Kohaus for excellent technical assistance and N. Gov for insightful discussions on the force model. Special thanks go to R. Kurre from the integrated Bioimaging Facility Osnabrueck (iBIOs, University of Osnabrück) for help with LLM. This work was supported by funds from the DFG to M.G. (EXC-1003; GA 2268/2-1, CRC1348/A06, CRC944/P22), M.M. (EXC-1003/FF-2015-07), J.K. (CRC1348/A02, CRC944/P5) and V.G. (CRC1348/A04, CRC1009/A06) and the Medical Faculty of the University of Münster to M.G. (IMF IGA-121610) and M.M. (IZKF Mat2/019/16).
Supplementary Information, Supplementary Figures 1–6 and Supplementary References 1–84.
Single-cell trace depicting two-mode migration. NIH 3T3 cell was transfected with a cytosolic reference. Centre of mass is used to determine cell trace. Scale bar is 20 µm.
Lattice lightsheet of NIH 3T3 fibroblast. NIH 3T3 cell was transfected with f-tractin and imaged using LLM. Note extension–retraction cycles at the leading edge. Scale bar is 10 µm.
Lattice lightsheet of seed-like structure at retracting lamellipodium. NIH 3T3 cell transfected with f-tractin and imaged using LLM. Nascent lamellipodium appears at the base of retracting lamellipodium. Scale bar is 5 µm.
Lattice lightsheet of biosensor versus actin at leading edge. NIH 3T3 cell transfected with f-tractin (green) and biosensor (magenta), imaged using LLM. Videos depict 3D reconstruction (left), x/z re-slice (middle) and x/y re-slice (right). Scale bar (left, right) 5 µm, (middle) 2 µm.
Lattice lightsheet of biosensor versus paxillin at leading edge. NIH 3T3 fibroblast transfected with the FA marker paxillin (green) and the curvature-sensitive biosensor (magenta). Videos depict 3D reconstruction (left), x/z re-slice (middle) and x/y re-slice (right). Scale bar (left) 5 µm, (middle, right) 2 µm.
Minimal model of LE re-initiation. From left to right, simulation with default settings, in the absence of myosin-dependent pulling forces, in the absence of positive feedback loop and in the absence of adhesion.
Addition of ML-7 aborts lamellipodial re-initiation. Cell was transfected with a marker for filamentous actin (f-tractin). Note the loss of lamellipodial extension–retraction cycles, but not of stress fibres, on addition of ML-7. Scale bar is 20 µm.
Cell plated on Y-shaped micropattern shows continuous lamellipodium surrounding the whole cell. Cell plated on fibronectin-coated Y-shaped micropattern and transfected with f-tractin (red) and a cytosolic reference (green). Note lamellipodium enclosing the whole cell circumference. Scale bar is 10 µm.
Massive overexpression of I-BAR domain alters migration pattern. NIH 3T3 cells were transfected with a cytosolic marker (left) or the I-BAR domain (right) and imaged 20 h post-transfection. Scale bar is 20 µm.
Transition of migration pattern with increase of I-BAR levels. Starting 5 h post-transfection, images of NIH 3T3 cell transfected with I-BAR domain were taken for 15 h. Note loss of motion persistence as I-BAR levels increase with time. Scale bar is 20 µm.