Epithelial layer jamming in breast cancer cell migration

乳腺癌细胞迁移中的上皮层干扰

• 批准号: 9329295
• 负责人: Jeffrey J Fredberg
• 金额: $ 74.3万
• 依托单位: HARVARD SCHOOL OF PUBLIC HEALTH
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-09-23 至 2020-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9329295
• 关键词: Adhesions; Adhesives; Affect; Alpha Cell; Blood Circulation; Breast Cancer Cell; Breast Cancer cell line; Breast Epithelial Cells; Cell Adhesion; Cell Line; Cell Shape; Cell-Cell Adhesion; Cells; Core Facility; Crowding; Data; Development; Disease Progression; Duct (organ) structure; E-Cadherin; Environment; Epithelial; Freezing; Heterogeneity; Individual; Laboratories; Lead; Link; Liquid substance; MCF10A cells; Maintenance; Malignant - descriptor; Malignant Neoplasms; Mammary Neoplasms; Measures; Mechanics; Motion; Neoplasm Circulating Cells; Non-Malignant; Organogenesis; Patient-Focused Outcomes; Pattern Formation; Phase; Phenotype; Physics; Play; Population; Property; Proteins; Role; Shapes; Side; Small Interfering RNA; Snails; Solid; Speed; Testing; Therapeutic Intervention; Thinking; Traction; Tumor Cell Migration; Tumor stage; cancer cell; cancer prevention; cancer stem cell; cancer therapy; cell motility; design; epithelial to mesenchymal transition; experimental study; indexing; insight; kinematics; knock-down; lens; malignant breast neoplasm; migration; monolayer; movie; neoplastic cell; novel; novel strategies; oncology; physical science; public health relevance; stem; stemness; theories; tumor; tumor progression; virtual

 DESCRIPTION (provided by applicant): Theoretical advances and experimental evidence from our laboratories now establish that migration of the constituent cell within the non-malignant epithelial cellular layer becomes dominated by physical interactions with nearest neighbors in a manner that is consistent with cell jamming. With changes of cellular crowding, cell-cell adhesion, or cooperative cellular propulsion, the confluent cellular collective can undergo a transition from a solid-like jammed phase in which cells become virtually frozen in place, to a fluid-like, unjammed phase in which cells readily exchange places and flow. The theory of critical scaling exponents predicts that the transition from solid-like jammed to fluid-lke unjammed phases is promoted by increased cell adhesive forces and linked to changes in cell shape. This theoretical prediction comprises our central hypothesis. Importantly, predictions from this theory are paradoxical to classical thinking but are borne out nevertheless by our preliminary data. Hence, this theory of cell jamming brings with it a new mechanism and a new physical picture of breast cancer cell migration. To test this theory, in Aim 1 we will characteriz jamming dynamics in a selected subset of the 9 breast cancer cell lines comprising the Bioresource Core Facility of the Physical Sciences-Oncology Network. In Aim 2 we will assess how cell-cell adhesion affects jamming with a specific focus on the changes in cellular adhesion that occur during the epithelial-to-mesenchymal transition (EMT). In Aim 3 we will investigate how the presence of cancer stem cells influence cellular jamming and collective motion. Impact: A key step in cancer progression is collective tumor cell migration, but how each individual cell coordinates its migration with that of immediate neighbors has defied mechanistic understanding. Here we propose experiments designed to unveil basic physics of collective cellular migration in early stages of tumor progression. Data derived from a comprehensive suite of experimental probes -cellular motions, traction forces, intercellular forces1,2,4,7-9 and cellular shapes- will be critically viewed through the lens of a novel theory of critical scaling.13,14 This theory of cell jamming is mechanistic, non-trivial, and counterintuitive. If supported by our data, it will not represent an incremental advance. Rather, it may provide important new insights concerning the physics of cancer progression, and, because its predictions are counterintuitive and paradoxical, it may lead to novel strategies for cancer treatment or prevention.

 描述（由申请人提供）：我们实验室的理论进展和实验证据现在确定，非恶性上皮细胞层内的组成细胞的迁移由与最近邻的物理相互作用主导，其方式与细胞干扰一致。随着细胞拥挤、细胞-细胞粘附或协同细胞推进的变化，汇合的细胞集合体可以经历从固体状堵塞阶段到流体状未堵塞阶段的转变，在固体状堵塞阶段中，细胞几乎被冻结在适当的位置，在流体状未堵塞阶段中，细胞容易交换位置和流动。临界标度指数理论预测，从固体状堵塞到流体状未堵塞相的转变是由细胞粘附力的增加促进的，并与细胞形状的变化有关。这个理论预测构成了我们的中心假设。重要的是，从这个理论的预测是自相矛盾的经典思维，但证实了我们的初步数据。因此，这种细胞干扰理论带来了乳腺癌细胞迁移的新机制和新的物理图像。为了测试这一理论，在目标1中，我们将在9个乳腺癌细胞系的选定子集中表征干扰动力学，所述乳腺癌细胞系包括物理科学-肿瘤学网络的生物资源核心设施。在目标2中，我们将评估细胞-细胞粘附如何影响干扰，特别关注上皮-间充质转化（EMT）期间发生的细胞粘附变化。在目标3中，我们将研究癌症干细胞的存在如何影响细胞干扰和集体运动。影响力：癌症进展的一个关键步骤是集体肿瘤细胞迁移，但每个细胞如何协调其迁移与近邻的机制的理解。在这里，我们提出了旨在揭示集体细胞迁移在肿瘤进展的早期阶段的基本物理实验。从一整套实验探针中获得的数据-细胞运动、牵引力、细胞间力1、2、4、7-9和细胞形状-将通过一种新的临界缩放理论的透镜进行批判性观察。13、14这种细胞干扰理论是机械的、非平凡的和违反直觉的。如果有我们的数据支持，它将不会代表一个渐进的进步。相反，它可能会提供有关癌症进展物理学的重要新见解，而且，因为它的预测是违反直觉和自相矛盾的，它可能会导致癌症治疗或预防的新策略。