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Endocytic reawakening of motility in jammed epithelia

Nature Materials volume 16, pages 587–596 (2017)Cite this article

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Abstract

Dynamics of epithelial monolayers has recently been interpreted in terms of a jamming or rigidity transition. How cells control such phase transitions is, however, unknown. Here we show that RAB5A, a key endocytic protein, is sufficient to induce large-scale, coordinated motility over tens of cells, and ballistic motion in otherwise kinetically arrested monolayers. This is linked to increased traction forces and to the extension of cell protrusions, which align with local velocity. Molecularly, impairing endocytosis, macropinocytosis or increasing fluid efflux abrogates RAB5A-induced collective motility. A simple model based on mechanical junctional tension and an active cell reorientation mechanism for the velocity of self-propelled cells identifies regimes of monolayer dynamics that explain endocytic reawakening of locomotion in terms of a combination of large-scale directed migration and local unjamming. These changes in multicellular dynamics enable collectives to migrate under physical constraints and may be exploited by tumours for interstitial dissemination.

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Figure 1: RAB5A promotes coherent, ballistic motion of jammed epithelia.
Figure 2: RAB5A alters junctional topology, tension and monolayer rigidity.
Figure 3: Endomembrane trafficking mediates RAB5A-induced collective motility.
Figure 4: RAB5A promotes polarized cell protrusions and traction forces.
Figure 5: RAB5A induces a collective flowing liquid mode of locomotion.
Figure 6: Biological consequences of RAB5-induced flowing liquid mode of motion.

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Acknowledgements

Work is supported by grants from the following agencies: Associazione Italiana per la Ricerca sul Cancro (AIRC #10168 and #18621), MIUR (the Italian Ministry of University and Scientific Research), the Italian Ministry of Health, Ricerca Finalizzata (RF0235844), Worldwide Cancer Research (AICR-14-0335), and the European Research Council (Advanced-ERC-#268836) (to G.S.); the Italian Ministry of Education and Research, Futuro in Ricerca Project ANISOFT (RBFR125H0M) (to R.C. and F.G.); Spanish Ministry of Economy and Competitiveness (BFU2012-38146), the Generalitat de Catalunya (2014-SGR-927), and the European Research Council (StG-CoG-616480) (to X.T.). C.M. was supported by Fondazione Umberto Veronesi. S.C. was supported by an AIRC fellowship. M.B. and T.L. were supported by funding from ETH-grant ETH-12 15-1.

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Author notes

  1. Chiara Malinverno and Salvatore Corallino: These authors contributed equally to this work.

Authors and Affiliations

  1. IFOM-FIRC Institute of Molecular Oncology, Via Adamello, 16, 20139 Milan, Italy

    Chiara Malinverno, Salvatore Corallino, Qingsen Li, Andrea Disanza, Emanuela Frittoli, Amanda Oldani, Emanuele Martini, Gianluca Deflorian, Galina V. Beznoussenko, Dario Parazzoli, Paolo Maiuri & Giorgio Scita

  2. Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, Università degli Studi di Milano, I-20090 Segrate, Italy

    Fabio Giavazzi & Roberto Cerbino

  3. ETH Zurich, Laboratory of Thermodynamics in Emerging Technologies, Sonneggstrasse 3, 8092 Zurich, Switzerland

    Martin Bergert, Tobias Lendenmann, Dimos Poulikakos & Aldo Ferrari

  4. Institut Curie, 26 rue d’Ulm 75248 Paris Cedex 05, France

    Marco Leoni

  5. Institute of Molecular and Cell Biology (IMCB), A(∗)STAR, Singapore 138673, Singapore

    Kok Haur Ong & Weimiao Yu

  6. Institute for Bioengineering of Catalonia, Barcelona, Barcelona 08028, Spain

    Marina Uroz & Xavier Trepat

  7. Catalan Institution for Research and Advanced Studies (ICREA), 08010 Barcelona, Spain

    Marina Uroz & Xavier Trepat

  8. CIBER de Bioingeniería, Biomateriales y Nanomedicina (CIBER-BBN), 28029 Madrid, Spain

    Marina Uroz & Xavier Trepat

  9. Facultat de Medicina, Universitat de Barcelona, 08036 Barcelona, Spain

    Marina Uroz & Xavier Trepat

  10. Dipartimento di Oncologia e Emato-Oncologia, Università degli Studi di Milano, I-20133 Milan, Italy

    Giorgio Scita

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  1. Chiara Malinverno
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Contributions

C.M. and S.C. designed and performed experiments, interpreted the data, and generated all the cell biological and molecular biological tools and reagents; F.G. analysed all time-lapse experiments, interpreted the data, and designed the computational model; M.B. and T.L. performed traction force microscopy experiments, and interpreted and analysed data; Q.L. designed and built micro-fabricated channels and performed AFM experiments; M.L. contributed to the development of the computational model and to its interpretation; A.D., A.O., E.M. and D.Parazzoli performed laser nano-scissor experiments of EGFP-E-cadherin and interpreted data migration data; E.F. performed immunofluorescence experiments; D.Poulikakos designed and interpreted CIV and cTFM experiments; K.H.O. and W.Y. executed the semi-automated tracking of cell shape and size; G.D. performed zebrafish experiments; G.V.B. performed electron microscopy analysis; M.U. performed traction force experiments, and interpreted and analysed data; X.T. designed traction force experiments, and helped developing the computational model and writing the paper; P.M. designed analytical tools, interpreted collective migration experiments and help in developing the computational model; A.F., R.C. and G.S. designed the research, analysed and interpreted the data and wrote the paper. Each author contributed to writing the paper.

Corresponding authors

Correspondence to Fabio Giavazzi, Aldo Ferrari, Roberto Cerbino or Giorgio Scita.

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The authors declare no competing financial interests.

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Malinverno, C., Corallino, S., Giavazzi, F. et al. Endocytic reawakening of motility in jammed epithelia. Nature Mater 16, 587–596 (2017). https://doi.org/10.1038/nmat4848

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