TY - JOUR
T1 - Nuclear positioning facilitates amoeboid migration along the path of least resistance
AU - Renkawitz, Jörg
AU - Kopf, Aglaja
AU - Stopp, Julian
AU - de Vries, Ingrid
AU - Driscoll, Meghan K.
AU - Merrin, Jack
AU - Hauschild, Robert
AU - Welf, Erik S.
AU - Danuser, Gaudenz
AU - Fiolka, Reto
AU - Sixt, Michael
N1 - Funding Information:
Acknowledgements We thank F. Gärtner, E. Kiermaier and A. Casano for discussions and critical reading of the manuscript, A. Leithner for primary T cells, A. Reversat for LMR7.5 cell cultures, J. Schwarz and M. Mehling for sharing microfluidics knowledge, K. M. Dean for assistance with light-sheet imaging, T. Goddard from UCSF ChimeraX (P41-GM103311) for assistance with 3D rendering, and the Scientific Service Units of IST Austria for support. This work was supported by the European Research Council (ERC StG 281556 and CoG 724373), a grant from the Austrian Science Foundation (FWF) and the FWF DK ‘Nanocell’ to M.S., National Institutes of Health awards (F32GM116370, K25CA204526) to M.K.D. and E.S.W., the Cancer Prevention Research Institute of Texas recruitment award (R1225) to G.D., the Cancer Prevention Research Institute of Texas recruitment award (RR160057) to R.F., ISTFELLOW funding from the People Programme (Marie Curie Actions) of the European Union's Seventh Framework Programme (FP7/2007-2013) under REA grant agreement no. 291734 to J.R., and an EMBO long-term fellowship (ALTF 1396-2014) co-funded by the European Commission (LTFCOFUND2013, GA-2013-609409) to J.R.
Publisher Copyright:
© 2019, The Author(s), under exclusive licence to Springer Nature Limited.
PY - 2019/4/25
Y1 - 2019/4/25
N2 - During metazoan development, immune surveillance and cancer dissemination, cells migrate in complex three-dimensional microenvironments1–3. These spaces are crowded by cells and extracellular matrix, generating mazes with differently sized gaps that are typically smaller than the diameter of the migrating cell4,5. Most mesenchymal and epithelial cells and some—but not all—cancer cells actively generate their migratory path using pericellular tissue proteolysis6. By contrast, amoeboid cells such as leukocytes use non-destructive strategies of locomotion7, raising the question how these extremely fast cells navigate through dense tissues. Here we reveal that leukocytes sample their immediate vicinity for large pore sizes, and are thereby able to choose the path of least resistance. This allows them to circumnavigate local obstacles while effectively following global directional cues such as chemotactic gradients. Pore-size discrimination is facilitated by frontward positioning of the nucleus, which enables the cells to use their bulkiest compartment as a mechanical gauge. Once the nucleus and the closely associated microtubule organizing centre pass the largest pore, cytoplasmic protrusions still lingering in smaller pores are retracted. These retractions are coordinated by dynamic microtubules; when microtubules are disrupted, migrating cells lose coherence and frequently fragment into migratory cytoplasmic pieces. As nuclear positioning in front of the microtubule organizing centre is a typical feature of amoeboid migration, our findings link the fundamental organization of cellular polarity to the strategy of locomotion.
AB - During metazoan development, immune surveillance and cancer dissemination, cells migrate in complex three-dimensional microenvironments1–3. These spaces are crowded by cells and extracellular matrix, generating mazes with differently sized gaps that are typically smaller than the diameter of the migrating cell4,5. Most mesenchymal and epithelial cells and some—but not all—cancer cells actively generate their migratory path using pericellular tissue proteolysis6. By contrast, amoeboid cells such as leukocytes use non-destructive strategies of locomotion7, raising the question how these extremely fast cells navigate through dense tissues. Here we reveal that leukocytes sample their immediate vicinity for large pore sizes, and are thereby able to choose the path of least resistance. This allows them to circumnavigate local obstacles while effectively following global directional cues such as chemotactic gradients. Pore-size discrimination is facilitated by frontward positioning of the nucleus, which enables the cells to use their bulkiest compartment as a mechanical gauge. Once the nucleus and the closely associated microtubule organizing centre pass the largest pore, cytoplasmic protrusions still lingering in smaller pores are retracted. These retractions are coordinated by dynamic microtubules; when microtubules are disrupted, migrating cells lose coherence and frequently fragment into migratory cytoplasmic pieces. As nuclear positioning in front of the microtubule organizing centre is a typical feature of amoeboid migration, our findings link the fundamental organization of cellular polarity to the strategy of locomotion.
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UR - http://www.scopus.com/inward/citedby.url?scp=85063938496&partnerID=8YFLogxK
U2 - 10.1038/s41586-019-1087-5
DO - 10.1038/s41586-019-1087-5
M3 - Article
C2 - 30944468
AN - SCOPUS:85063938496
SN - 0028-0836
VL - 568
SP - 546
EP - 550
JO - Nature
JF - Nature
IS - 7753
ER -