Adhesive crosstalk in collective tumor cell invasion

大多数癌症死亡率的出现是因为肿瘤细胞离开其原发部位，引起转移性肿瘤。 其他器官的肿瘤虽然肿瘤进展有许多复杂的生物学方面， 癌转移、局部浸润穿过上皮基底膜和原发肿瘤的迁移 细胞通过细胞外基质（ECM）进入淋巴管和血管通道显然是一个关键的早期 步肿瘤细胞可以单独或成组侵入和迁移。病理性和体内累积 实验证据现在表明，肿瘤细胞迁移的最常见形式可能是集体迁移， 组虽然我们已经了解了大量的细胞生物学，生物化学和生物物理机制， 在2D、3D和体内单个细胞迁移的基础上，我们对细胞迁移的调控的理解是： 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 它们的细胞迁移受许多力的支配：被动力（弹性力和粘附力）、摩擦力、 （对细胞滑过彼此和细胞滑过基底的阻力）、活性（渗透性和渗透性）、 收缩力）和作用在下面或周围ECM上的牵引力。哪些力量对于 肿瘤细胞的集体迁移以及如何迁移尚不清楚。这项提议的首要假设是， 细胞-ECM和细胞-细胞相互作用将通过粘附串扰联合收割机来调节肿瘤聚集 通过改变运动和力产生的协同性来实现细胞迁移。为了验证这一假设， 开发了计算工具和2D和体内3D实验模型， 当一组肿瘤细胞组织起来集体迁移通过肿瘤时， 间质和肿瘤上皮内。我们解决这个问题的方法是迭代的：使用计算 模拟，以告知各种力量如何有助于组织和运动的实验测试， 肿瘤细胞的集合体。我们提出了四个具体目标，使用这些工具来解决这个问题： 1.为了确定一个完整的实验和计算模型，肿瘤细胞的内在变化， 粘附影响集体迁移。目标2.为了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.为了确定细胞-细胞和细胞-ECM力如何影响细胞的性质， 在临床相关的原发性人乳腺肿瘤样本中肿瘤细胞集体迁移。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.