Collective Cell Motility Promotes Chemotactic Prowess and Resistance to Chemorepulsion
Collective Cell Motility Promotes Chemotactic Prowess and Resistance to Chemorepulsion
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DOI：
10.1016/j.cub.2014.11.030
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发表时间：
2015-01-19
期刊：
影响因子：
9.2
通讯作者：
Dupre, Loic
中科院分区：
文献类型：
--
作者：
Malet-Engra, Gema;Yu, Weimiao;Dupre, Loic
集体细胞迁移是一种广泛存在的生物现象，即高度协调的贴壁细胞群以极化方式移动[1,2]。这种迁移模式是组织发育和修复过程中形态发生以及实体瘤播散[1]的标志。淋巴细胞恶性肿瘤除了作为孤立细胞循环外，还可以作为多细胞聚集体聚集成组织。然而，在趋化因子梯度的背景下，恶性淋巴细胞是否能够协调它们的运动尚不清楚。在这里，我们表明，暴露于CCL19或CXCL12梯度后，恶性B淋巴细胞和T淋巴细胞聚集成簇，定向迁移，并表现出比单个细胞更广泛的趋化敏感性。物理模型概括了簇运动统计数据，并表明簇内细胞内聚导致噪声降低和方向性增强。定量图像分析显示，集群迁移运行周期性地被短暂的旋转和有利于领导细胞更替的随机阶段打断。此外，CCR7在领导细胞中的内化伴随着前伸后缩、极性丧失以及随后被新的领导细胞取代。这些机制确保了持续的向前迁移和对化学排斥的抵抗，化学排斥是暴露于陡峭ccr19梯度下的个体细胞的行为，依赖于CCR7的内吞作用。因此，协调的集群动力学赋予了不同的趋化特性，突出了淋巴样细胞迁移的意想不到的特征。
Collective cell migration is a widespread biological phenomenon, whereby groups of highly coordinated, adherent cells move in a polarized fashion [1, 2]. This migration mode is a hallmark of tissue morphogenesis during development and repair and of solid tumor dissemination [1]. In addition to circulating as solitary cells, lymphoid malignancies can assemble into tissues as multicellular aggregates [3]. Whether malignant lymphocytes are capable of coordinating their motility in the context of chemokine gradients is, however, unknown. Here, we show that, upon exposure to CCL19 or CXCL12 gradients, malignant B and T lymphocytes assemble into clusters that migrate directionally and display a wider chemotactic sensitivity than individual cells. Physical modeling recapitulates cluster motility statistics and shows that intracluster cell cohesion results in noise reduction and enhanced directionality. Quantitative image analysis reveals that cluster migration runs are periodically interrupted by transitory rotation and random phases that favor leader cell turnover. Additionally, internalization of CCR7 in leader cells is accompanied by protrusion retraction, loss of polarity, and the ensuing replacement by new leader cells. These mechanisms ensure sustained forward migration and resistance to chemorepulsion, a behavior of individual cells exposed to steep CCL19 gradients that depends on CCR7 endocytosis. Thus, coordinated cluster dynamics confer distinct chemotactic properties, highlighting unexpected features of lymphoid cell migration.