Collective cellular migration, cell jamming, and matrix adhesion in breast cancer model systems

项目摘要/摘要 乳腺癌是美国第四大死因。乳腺癌的无节制发展和 治疗抵抗导致患者预后不良。最近的研究表明，异常生长是 不是侵袭性癌症生长的主要媒介，而是癌细胞迁移的能力。 此外，迁移的类型也很重要：细胞聚集在一起迁移已被证明是 比单个细胞迁移更具侵袭性。因此，了解细胞集体迁移的原因和方式 可能会导致新的治疗干预措施，更好地防止乳腺癌的进展。我们的团队 最近发现了一种现象，细胞堵塞，可以解释上皮细胞的集体迁移 单层。细胞的集体运动可以被描述为非迁移性的，对于被堵塞的 状态，或非拥堵状态下的迁徙和流动状态。细胞干扰的理论说明了细胞-细胞 黏附和细胞皮质张力相互作用，控制细胞形状的变化，调节集体细胞 迁移。然而，它不包括细胞-基质相互作用的贡献。这是一个关键的差距 理解集体迁移，因为细胞-基质黏附蛋白直接偶联到细胞-细胞 黏附蛋白。这项提案将测试目前开发的乳房蜂窝干扰指标。 肿瘤的发生，并进一步测试细胞-基质黏附的增加如何调节集合体 行为。在目标1中，我们将测试正常和恶性乳腺上皮单层模型以及它们的 通过测量细胞-细胞作用力、细胞-基质作用力和细胞动力学，有堵塞(或保持不堵塞)的趋势 动议。我们的团队已经证明，细胞间粘附力的增加会导致细胞不受干扰。一个可能的 细胞-细胞黏附改变的机制是增强abl信号，它已被证明调节侵袭性。 癌细胞的运动和细胞-细胞黏附蛋白的差异激活。目标2将测试ABL的贡献 激酶活性对细胞畅通的影响。此外，由于细胞-细胞黏附本质上耦合到细胞-基质 粘连，了解细胞-基质粘连在3D模型中的作用，对于开发 蜂窝畅通如何导致集体迁移的完整物理图景。因此，目标3将利用 正常和恶性乳腺上皮细胞的球体作为细胞模型将逃脱3D 在调节细胞-基质黏附时，通过不受干扰和铺展来形成椭圆形。这项拟议的工作将 阐明乳腺上皮集体迁移的物理机制(S)，从而可能导致 乳腺癌治疗发展的新方向，从靶向HER2等生长因子到靶向 迁徙因素。

PROJECT SUMMARY/ABSTRACT Breast cancer the 4th leading cause of death in the US. Unchecked progression of breast cancer and therapeutic resistance leads to poor patient prognosis. Recent studies have suggested that aberrant growth is not the primary mediator of aggressive cancer growth, rather, the ability of cancer cells to migrate. Furthermore, the type of migration is also important: cell cohesively migrating together have been shown to be more invasive than single cells migrating. Therefore, understanding why and how cells collectively migrate could lead to new therapeutic interventions that would better prevent breast tumor progression. Our group recently discovered a phenomenon, cellular jamming, that may explain collective migration in epithelial monolayers. Collective cellular motion could be either described as non-migratory and solid-like for a jammed state, or migratory and fluid-like for an unjammed state. The theory of cell jamming shows how cell-cell adhesion and cell cortical tension interact to control changes of cell shape and to regulate collective cellular migration. It does not, however, include contributions by cell-matrix interactions. This is a critical gap in understanding collective migration, because cell-matrix adhesion proteins are directly coupled to cell-cell adhesion proteins. This proposal will test the currently developed metrics of cellular jamming in breast tumorigenesis and furthermore, test how the addition of cell-matrix adhesions would modulate collective behavior. In Aim 1, we will test models of both normal and malignant breast epithelial monolayers and their tendency to jam (or remain unjammed) by measuring cell-cell forces, cell-matrix forces, and kinetics of cellular motion. Our group has shown that increases in cell-cell adhesion forces leads to unjamming cells. A possible mechanism of altered cell-cell adhesion is enhanced Abl signaling, which has been shown to regulate invasive cancer cell motility and differential cell-cell adhesion protein activation. Aim 2 will test the contributions of Abl kinase activity to cellular unjamming. Furthermore, as cell-cell adhesions are intrinsically coupled to cell-matrix adhesions, understanding contributions from cell-matrix adhesions in a 3D model, is critical to developing a complete physical picture of how cellular unjamming leads to collective migration. Therefore, Aim 3 will utilize spheroids of both normal and malignant breast epithelial cells as a model of cells would escape from a 3D spheroid by unjamming and spreading when modulating cell-matrix adhesions. This proposed work will elucidate the physical mechanism(s) by which breast epithelial collectives migrate, and thus could lead to a new direction in breast cancer therapy development, from targeting growth factors such as HER2 to targeting migratory factors.