Adhesive crosstalk in collective tumor cell invasion

大多数癌症死亡是因为肿瘤细胞离开其原发部位，导致转移 其他器官的肿瘤。虽然肿瘤进展有许多复杂的生物学方面导致 癌症转移、上皮基底膜局部侵袭和原发肿瘤迁移 细胞通过细胞外基质（ECM）进入淋巴和血管通道显然是早期的关键 步骤。肿瘤细胞可以单独或成群地侵入和迁移。病理和体内积累 现在的实验证据表明，肿瘤细胞迁移的最常见形式可能是作为一个集体 组。虽然我们已经了解了大量关于细胞生物学、生化和生物物理机制的知识 在 2D、3D 和体内单个细胞迁移的基础上，我们对调节的理解 癌症转移中的集体细胞迁移处于早期阶段。将细胞组织成集体组 它们的细胞迁移受到多种力的控制：被动力（弹性力和粘附力）、摩擦力 （抵抗细胞相互滑动和细胞在基底上滑动），活性（突出和 收缩力），以及作用在下面或周围 ECM 上的牵引力。哪些力量至关重要 肿瘤细胞的集体迁移以及如何迁移尚不清楚。该提案的总体假设 细胞-ECM 和细胞-细胞相互作用将通过粘附串扰结合起来调节肿瘤集体 通过改变运动和力产生的协同性来实现细胞迁移。为了检验这个假设，我们有 开发了计算工具以及 2D 和体内 3D 实验模型来测量各种物理 当一组肿瘤细胞组织在肿瘤中集体迁移时，它们内部和周围的力 间质和肿瘤上皮内。我们解决问题的方法是迭代的：使用计算 模拟为各种力如何影响物体的组织和运动的实验测试提供信息 肿瘤细胞的集体群体。我们提出使用这些工具来解决这个问题的四个具体目标： 1. 确定肿瘤细胞内在变化的综合实验和计算模型 粘附影响集体迁移。目标 2. 确定肿瘤环境的变化如何影响 肿瘤细胞的集体迁移。目标 3. 确定细胞-细胞和细胞-ECM 力如何影响自然 临床相关的原发性人类乳腺肿瘤样本中肿瘤细胞集体迁移的研究。目标 4. 发展 组织中集体细胞迁移动力学的计算模型。

The majority of cancer mortality arises because tumors cells leave their primary site, giving rise to metastatic tumors in other organs. While there are many and complex biologic aspects of tumor progression leading to cancer metastasis, local invasion through the basement membrane of epithelia and migration of primary tumor cells through the extracellular matrix (ECM) to access lymphatic and vascular channels is clearly a critical early step. Tumor cells can invade and migrate individually or as groups. Accumulating pathologic and in vivo experimental evidence now indicates that the most common form of tumor cell migration is likely as a collective group. While we have learned a great deal about the cell biologic, biochemical, and biophysical mechanisms underlying the migration of individual cells in 2D, 3D and in vivo, our understanding about the regulation of collective cell migration in cancer metastasis is at an early stage. Organization of cells into collective groups and their migration of cells is governed by a number of forces: passive (elastic and adhesive forces), frictional (resistance to cells sliding past one another and cells sliding across a substrate), active (protrusive and contractile forces), and traction forces upon the underlying or surrounding ECM. Which forces are critical for the collective migration of tumor cells, and how, is not understood. The overarching hypothesis of this proposal is that cell-ECM and cell-cell interactions will combine through adhesion crosstalk to modulate tumor collective cell migration by altering cooperativity of motion and force generation. To test this hypothesis we have developed computational tools and 2D and in vivo 3D experimental models that measure various physical forces within and around a group of tumor cells as they organize to migrate in a collective through the tumor stroma and within the tumor epithelium. Our approach to the problem is iterative: using computational simulations to inform experimental testing of how various forces contribute to the organization and motion of collective groups of tumor cells. We propose four specific aims using these tools to address this problem: Aim 1. To determine an integrated experimental and computational model of how tumor cell-intrinsic changes in adhesion influence collective migration. Aim 2. To determine how changes in the tumor environment affect collective migration of tumor cell. Aim 3. To determine how cell-cell and cell-ECM forces influence the nature of tumor cell collective migration in clinically relevant primary human breast tumor samples. Aim 4. To develop a computational model of collective cell migration dynamics in tissues.