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Tissue fluidification and collective motility are pivotal in regulating embryonic morphogenesis, wound healing and tumor metastasis. These processes frequently require that each cell constituent of a tissue coordinates its migration activity and directed motion through the oriented extension of lamellipodia cell protrusions, promoted by RAC1 activity. While the upstream RAC1 regulators in individual migratory cells or leader cells during invasion or wound healing are well characterized, how RAC1 is controlled in follower cells remains unknown. Here, we identify a novel MYO6-DOCK7 axis that is critical for spatially restriction of RAC1 activity in a planar polarized fashion in model tissue monolayers. The MYO6-DOCK7 axis specifically controls the extension of cryptic lamellipodia required to drive tissue fluidification and cooperative mode motion in otherwise solid and static carcinoma cell collectives.HighlightsCollective motion of jammed epithelia requires myosin VI activityThe MYO6-DOCK7 axis is critical to restrict the activity of RAC1 in a planar polarized fashionMYO6-DOCK7-RAC1 activation ensures long-range coordination of movements by promoting orientation and persistence of cryptic lamellipodiaMyosin VI overexpression is exploited by infiltrating breast cancer cells

Under homeostatic conditions, mature epithelia are locked in a kinetically-silent, jammed state. During wound repair or branching morphogenesis epithelia must unjam and acquire liquid-like properties. These events might be recapitulated in the transition from in situ to invasive cancer stages. How cells control this transition and how biologically relevant it is, however, remains unclear. Recently, we showed that altering RAB5A levels, a master regulator of endosomal trafficking, is sufficient to re-awaken motility in jammed epithelia, through ill-defined, endocytic-sensitive biochemical pathways. Here, we show that RAB5A promotes non-clathrin-dependent internalization of epidermal growth factor receptor that leads to the hyper-activation of endosomally-confined ERK1/2 and phosphorylation of the branched actin nucleator, WAVE2. This endo-ERK1/2 route, in turn, is critical to promote a flocking transition in epithelial monolayers and in differentiated normal mammary 3D cysts, where it further overcome proliferation arrest and to initiate bud morphogenesis. In 3D spheroid models of breast ductal carcinoma in situ (DCIS), instead, endo-ERK1/2-mediated unjamming causes the emergence of highly coordinated angular rotational motion, matrix remodelling and collective 3D invasion. Similarly, it promotes a flocking mode of collective dissemination ex vivo in slices of orthotopically-implanted DCIS. Thus, EGF-dependent activation of endosomal ERK1/2 is found to be the molecular determinant of unjamming via flocking transition: a powerful machinery that overcomes the kinetic and proliferation arrest of terminally differentiated epithelial cells, and promotes collective invasive programs of jammed carcinomas.