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

乳腺癌模型系统中的集体细胞迁移、细胞干扰和基质粘附

• 批准号: 9404520
• 负责人: Karin Chieh Wang
• 金额: $ 0.22万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2018-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9404520
• 关键词: Adhesions; Adhesives; Area; Basement membrane; Behavior; Biological Models; Breast; Breast Cancer Model; Breast Cancer therapy; Breast Epithelial Cells; Cancer Cell Growth; Cause of Death; Cell Shape; Cell model; Cell-Cell Adhesion; Cell-Matrix Junction; Cells; Collagen; Coupled; Development; ERBB2 gene; Epithelial; Extracellular Matrix; Faculty; Focal Adhesions; Gel; Goals; Growth; Growth Factor; Individual; Island; Kinetics; Laminin; Lead; Liquid substance; MCF10A cells; MDA MB 231; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Measurement; Measures; Mechanics; Mediator of activation protein; Membrane Proteins; Mentors; Modeling; Morphology; Motion; Patients; Phenotype; Phosphorylation; Phosphotransferases; Physics; Plant Roots; Platelet-Derived Growth Factor; Process; Proteins; Research; Research Personnel; Resistance; Role; Shapes; Signal Transduction; Solid; Structure; System; Testing; Therapeutic; Therapeutic Intervention; Traction; Training; Vinculin; Work; breast tumorigenesis; cancer cell; cancer invasiveness; cell motility; cohesion; condensed matter physics; improved; insight; interstitial; malignant breast neoplasm; mammary epithelium; migration; monolayer; neoplastic cell; novel; novel strategies; novel therapeutic intervention; outcome forecast; polyacrylamide gels; prevent; protein activation; theories; therapeutic development; therapy development; therapy resistant; three-dimensional modeling; tumor growth; tumor progression

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.

项目总结/摘要 乳腺癌是美国第四大死亡原因。乳腺癌的不受控制的进展， 治疗抗性导致患者预后差。最近的研究表明， 不是恶性肿瘤生长的主要介质，而是癌细胞迁移的能力。 此外，迁移的类型也很重要：细胞内聚迁移在一起已被证明是 比单个细胞迁移更具侵袭性。因此，了解细胞为什么以及如何集体迁移 可能会导致新的治疗干预，将更好地防止乳腺肿瘤的进展。我们集团 最近发现了一种现象，细胞堵塞，这可能解释集体迁移上皮细胞， 单层。集体细胞运动可以被描述为非迁移和固体状的堵塞， 状态，或者对于未堵塞的状态而言是迁移的和流体状的。细胞干扰的理论显示了细胞间 粘附和细胞皮层张力相互作用，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-基质粘附蛋白直接偶联到细胞-细胞 粘附蛋白该提案将测试目前开发的乳腺癌细胞干扰指标， 肿瘤发生，并进一步测试细胞-基质粘附的增加如何调节集体 行为在目标1中，我们将测试正常和恶性乳腺上皮单层的模型及其 通过测量细胞-细胞力、细胞-基质力和细胞的动力学， 议案我们的研究小组已经表明，细胞间粘附力的增加会导致细胞的不受干扰。一个可能 改变的细胞-细胞粘附的机制是增强的Abl信号传导，其已被证明调节侵袭性细胞粘附。 癌细胞运动性和差异细胞-细胞粘附蛋白激活。目标2将测试Abl的贡献 激酶活性对细胞解除干扰的影响。此外，由于细胞-细胞粘附与细胞-基质内在地偶联， 粘附，了解细胞-基质粘附在3D模型中的作用，对于开发 完整的物理图像，说明细胞如何解除干扰，导致集体迁移。因此，目标3将利用 作为细胞模型的正常和恶性乳腺上皮细胞的球状体将从3D模型中逃逸， 在调节细胞-基质粘附时，通过解除干扰和扩散来形成球状体。这项工作将 阐明乳腺上皮细胞集体迁移的物理机制，从而可能导致 乳腺癌治疗发展的新方向，从靶向生长因子如HER 2到靶向 迁移因素。