标题： 趋化性驱动的不稳定性支配着多细胞簇的大小、形状和迁移效率 显示英文标题

标题： Chemotaxis-Driven Instabilities Govern Size, Shape and Migration Efficiency of Multicellular Clusters

摘要： 多细胞簇的整体趋化性迁移在多种生理背景下是一种重要的现象，从胚胎发育到癌症转移均涉及此现象。 这类簇常常表现出有趣的形状动力学和不稳定性，但它们的物理起源、功能优势以及在整体趋化性迁移中的作用仍不清楚。 在这里，我们结合了计算建模和体外恶性淋巴细胞簇迁移的实验观察，以了解这些动态如何源自趋化性反应与细胞间相互作用之间的相互作用。 我们的基于细胞的计算模型整合了细胞的主动推进、运动接触抑制、趋化性吸引响应，以及细胞间的排列、粘附和排斥相互作用。 我们发现，在低浓度的趋化性吸引物梯度下，簇保持流体状态并维持一致的向前迁移。 然而，在超过一个阈值梯度的情况下，簇显示出由局部簇形状依赖的速度差异引起的不稳定性，这导致它们在垂直于梯度的方向上拉长并最终分裂。 与我们的体外数据对比显示，预测的簇不稳定性区域随着梯度增加而发生转变，并且在簇纵横比、取向和破裂频率等关键特征上达到了定量一致性。 这种不稳定性自然限制了多细胞聚集物的大小，此外，在不稳定性区域的簇显示出最佳的向前迁移速度，暗示了其体内功能意义。 我们的工作为趋化性簇的普遍不稳定性提供了有价值的见解，阐明了可能促成转移扩散的物理因素，并可以扩展到其他活性簇的活体或合成系统中。 显示英文摘要

摘要： The collective chemotaxis of multicellular clusters is an important phenomenon in various physiological contexts, ranging from embryonic development to cancer metastasis. Such clusters often display interesting shape dynamics and instabilities, but their physical origin, functional benefits, and role in overall chemotactic migration remain unclear. Here, we combine computational modeling and experimental observations of malignant lymphocyte cluster migration in vitro to understand how these dynamics arise from an interplay of chemotactic response and inter-cellular interactions. Our cell-based computational model incorporates active propulsion of cells, contact inhibition of locomotion, chemoattractant response, as well as alignment, adhesive, and exclusion interactions between cells. We find that clusters remain fluid and maintain cohesive forward migration in low chemoattractant gradients. However, above a threshold gradient, clusters display an instability driven by local cluster-shape dependent velocity differentials that causes them to elongate perpendicular to the gradient and eventually break apart. Comparison with our in vitro data shows the predicted transition to the cluster instability regime with increased gradient, as well as quantitative agreement with key features such as cluster aspect ratio, orientation, and breaking frequency. This instability naturally limits the size of multicellular aggregates, and, in addition, clusters in the instability regime display optimal forward migration speeds, suggesting functional implications in vivo. Our work provides valuable insights into generic instabilities of chemotactic clusters, elucidates physical factors that could contribute to metastatic spreading, and can be extended to other living or synthetic systems of active clusters.