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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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.
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) doi:10.1038/nmat4848
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