Competition Between Contractility and Surface Tension in Collective Cell Migration

生物细胞在健康生活期间以及在从伤口修复到癌症进展的组织变化期间的疾病期间都成组迁移。迁移可以恢复受损组织的正常功能，例如伤口修复，或者进一步促进疾病的传播，例如扩散的癌症。在伤口愈合和癌症中，细胞通常一起迁移，其中每个细胞的运动取决于其自身的主动收缩力及其与邻居的相互作用。由此产生的细胞运动可以有很大的不同--从一个类似固体的状态，其中每个细胞都保持靠近它的邻居，到一个类似流体的状态，其中每个细胞都自由地迁移经过它的邻居。在伤口愈合和癌症侵袭中均发生固体样和液体样迁移之间的转变，其原因尚不清楚。理论模型预测，这种转变取决于相邻细胞之间的粘附分子，而且，与直觉相反，更大的粘附会导致更像流体的行为。 这一预测是复杂的，因为一些与细胞间粘附相关的分子也会导致细胞收缩并拉向它们的邻居。这项工作将通过实验研究粘附和收缩对集体迁移的竞争作用，从而澄清我们对集体迁移的理解，并为如何促进伤口愈合或在癌症进展期间减少迁移提供新的见解。 PI将通过UW-Madison工程学院的夏季本科生研究体验（SURE）计划，从科学和工程领域代表性不足的群体中招募本科生。通过SURE项目，这些学生将获得研究经验，并将被鼓励攻读研究生课程。本研究将验证以下假设：固体到流体的转变是每个细胞内主动收缩张力与每个细胞-细胞界面处的粘附表面能之间的平衡的结果。为了量化细胞间粘附，本项目将使用严格的机械定义，表面张力。为了量化收缩，它将使用每个细胞内的收缩应力。表面张力和收缩应力将通过使用药理学抑制剂和适当信号传导途径的转染来调节，并且将通过使用最先进的光学显微镜和定量图像分析来测量它们。本研究的第一个目的是揭示细胞内表面张力是如何从每个细胞皮层中的肌动球蛋白收缩和每个细胞-细胞界面处的粘附连接之间的平衡中产生的。第二个目标是研究收缩力和表面张力如何共同调节多细胞运动。由此产生的数据将给出一个完整的说明集体细胞运动的力学，因此，他们将提供一个实验基础，测试理论的集体迁移的机制。

Biological cells migrate in groups both during healthy life and also during diseases during tissue changes ranging from wound repair to cancer progression. The migration can restore normal function of damaged tissue, as in wound repair, or further the spread of disease, as in a spreading cancer. In both wound healing and cancer, it is typical for cells to migrate together where each cell's motion depends its own active contractile forces and its interaction with neighbors. The resulting cellular motions can vary dramatically--from a solid-like state, where each cell remains close to its neighbors, to a fluid-like state, where each cell freely migrates past its neighbors. The transition between solid-like and fluid-like migration occurs in both wound healing and cancer invasion and its causes remain unclear. Theoretical models have predicted that the transition depends on the adhesion molecules between neighboring cells, and, counterintuitively, that greater adhesion causes a more fluid-like behavior. This prediction is complicated by the fact that some molecules associated with cell-cell adhesion also cause cells to contract and pull against their neighbors. The work will experimentally examine the competing roles of adhesion and contraction on collective migration, thereby clarifying our understanding of collective migration and providing new insights into how the migration may be promoted in wound healing or reduced during cancer progression. The PI will recruit undergraduate students from underrepresented groups in science and engineering through the Summer Undergraduate Research Experience (SURE) program in the College of Engineering at UW-Madison. Through the SURE program, these students will gain research experience and will be encouraged to pursue graduate studies.This research will test the hypothesis that the solid-to-fluid transition results from a balance between the active contractile tension inside each cell and the adhesive surface energy at each cell-cell interface. To quantify intercellular adhesion, this project will use a mechanically rigorous definition, the surface tension. To quantify contraction, it will use the contractile stress within each cell. Surface tension and contractile stress will be modulated by using pharmacological inhibitors and transfections of appropriate signaling pathways, and they will be measured by using state-of-the art optical microscopy and quantitative image analysis. The first objective of this research will reveal how the intracellular surface tension results from the balance between the actomyosin contraction in each cell's cortex and the adherens junctions at each cell-cell interface. The second objective will investigate how contractility and surface tension together regulate the multicellular motion. The resulting data will give a complete account of the mechanics of collective cellular motion, and thus they will provide an empirical basis for testing theories for the mechanisms of collective migration.