IFOM-FIRC Institute of Molecular Oncology, Via Adamello, 16 20139, Milan, Italy.
Università degli Studi di Milano, Dipartimento di Biotecnologie Mediche e Medicina Traslazionale, I-20090, Segrate, Italy.
Nat Mater. 2017 May;16(5):587-596. doi: 10.1038/nmat4848. Epub 2017 Jan 30.
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.
上皮细胞单层的动力学最近被解释为一种阻塞或刚性转变。然而，细胞如何控制这种相转变尚不清楚。在这里，我们表明 RAB5A，一种关键的内吞蛋白，足以在数十个细胞上诱导大规模的协调运动，并在其他动力学上被抑制的单层中产生弹道运动。这与牵引力的增加以及细胞突起的延伸有关，细胞突起与局部速度一致。从分子上看，抑制内吞作用、巨胞饮作用或增加流体流出会破坏 RAB5A 诱导的集体运动。一个基于机械连接张力的简单模型和一个用于自推进细胞速度的主动细胞重定向机制，确定了单层动力学的范围，该范围根据大尺度定向迁移和局部去阻塞的组合，解释了内吞作用重新唤醒运动的机制。这些细胞动力学的变化使细胞群体能够在物理约束下迁移，并可能被肿瘤用于间质扩散。
