Epithelial layer jamming in breast cancer cell migration

乳腺癌细胞迁移中的上皮层干扰

基本信息

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
项目类别：
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

项目摘要

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（由适用提供）：我们实验室的理论进步和实验证据现在确定，非理性上皮细胞层中组成细胞的迁移以与细胞堵塞一致的方式与最近的邻居的物理相互作用主导。随着细胞拥挤，细胞 - 细胞粘合剂或坐标细胞推进的变化，汇合的细胞集体可以从固体样堵塞的相过渡，其中细胞几乎被冷冻到位，转变为流体状的，未束缚的相位，在该相中，细胞易于交换位置和流动的位置和流动。临界缩放示例的理论预测，通过增加的细胞粘附力来促进从固体样堵塞到流体液体无骨的相位的过渡，并与细胞形状变化有关。这种理论预测由我们的中心假设组成。重要的是，该理论的预测是对古典思维的悖论，但通过我们的初步数据诞生。因此，这种细胞干扰的理论带来了一种新的机制和乳腺癌细胞迁移的新物理图片。为了检验这一理论，在AIM 1中，我们将在完成物理科学 - 综合网络的Bioresource核心设备的9个乳腺癌细胞系的选定子集中进行征服动力。在AIM 2中，我们将评估细胞 - 细胞粘合剂如何影响堵塞，以特定的重点对上皮 - 间质转变（EMT）期间发生的细胞粘合剂的变化。在AIM 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：癌症进展的关键步骤是集体肿瘤细胞迁移，但是每个单个细胞如何与直接邻居的迁移相协调其迁移已确定机械理解。在这里，我们提出的实验旨在在肿瘤进展的早期阶段揭示集体细胞迁移的基本物理。从实验问题的全面套件中得出的数据 - 细胞运动，牵引力，细胞间力1,2,4,7-9和细胞形状 - 将通过新颖的临界缩放理论的镜头进行认真观察。13,14这种细胞障碍理论是机械性的，非手术和反智能的。如果我们的数据支持，它将不会代表增量进步。相反，它可能会提供有关癌症进展物理学的重要新见解，并且由于其预测是违反直觉和自相矛盾的，因此可能会导致新的癌症治疗或预防策略。