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：
9767079
负责人：
Jeffrey J Fredberg
金额：
$ 58.81万
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/9767079
关键词：
3-Dimensional Adhesions Adhesives Affect 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（由申请人提供）：我们实验室的理论进展和实验证据现在证实，非恶性上皮细胞层内的组成细胞的迁移以与细胞干扰一致的方式由与最近邻居的物理相互作用主导。由于细胞拥挤、细胞间粘附或细胞协作推进的变化，汇合的细胞集体可以经历从细胞实际上冻结在原地的固体状堵塞相转变为流体状，细胞容易交换位置和流动的未堵塞相临界缩放指数理论预测，细胞粘附力的增加会促进从固体状堵塞相到流体状未堵塞相的转变，并且与细胞形状的变化有关。重要的是，该理论的预测与经典思维相悖，但我们的初步数据证实了这一理论，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物理图像。测试根据这一理论，在目标 1 中，我们将表征构成物理科学-肿瘤学网络生物资源核心设施的 9 种乳腺癌细胞系的选定子集中的干扰动态。在目标 2 中，我们将评估细胞间粘附如何影响干扰。特别关注上皮间质转化 (EMT) 过程中细胞粘附的变化。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。影响：癌症进展的一个关键步骤是肿瘤细胞的集体迁移，但每个单独的细胞如何与邻近的细胞协调迁移却无法从机制上理解。在这里，我们提出了旨在揭示早期集体细胞迁移的基本物理原理的实验。从一整套实验探针（细胞运动、牵引力、细胞间力1、2、4、7-9 和细胞形状）中获得的数据将通过批判性建模的新颖理论来批判性地观察。 13 ,14 这个理论细胞干扰是机械性的、非平凡的、违反直觉的，如果得到我们的数据的支持，它不会代表一种渐进的进步，相反，它可能会提供关于癌症进展的物理学的重要的新见解，而且，因为它的预测是违反直觉和矛盾的。，它可能会带来癌症治疗或预防的新策略。

项目成果

期刊论文数量（9）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

A theoretical model of collective cell polarization and alignment.

集体细胞极化和排列的理论模型。

DOI：
10.1016/j.jmps.2019.103860
发表时间：
2020-04-01
期刊：
Journal of the mechanics and physics of solids
影响因子：
5.3
作者：
Shijie He;Yoav Green;N. Saeidi;Xiaojun Li;J. Fredberg;B. Ji;L. Pismen
通讯作者：
L. Pismen

Erratum to: Elevated MTSS1 expression associated with metastasis and poor prognosis of residual hepatitis B-related hepatocellular carcinoma.

勘误表：MTSS1 表达升高与残留乙型肝炎相关肝细胞癌的转移和预后不良相关。

DOI：
发表时间：
2016-06-24
期刊：
影响因子：
0
作者：
Huang, Xiu;Huang, Zi;Xu, Bin;Chen, Zi;Re, Thomas Joseph;Zheng, Qi;Tang, Zhao;Huang, Xin
通讯作者：
Huang, Xin

Missing-in-metastasis B (MIM-B) combined with caveolin-1 promotes metastasis of hepatocellular carcinoma.

转移缺失 B (MIM-B) 联合 Caveolin-1 促进肝细胞癌转移。

DOI：
发表时间：
2017-11-10
期刊：
影响因子：
0
作者：
Huang, Xiu;Huang, Zi;Niu, Tao;Wu, Zhen;Xu, Bin;Xu, Yong;Huang, Xin;Zheng, Qi;Zhou, Jian;Chen, Zi;Tang, Zhao
通讯作者：
Tang, Zhao

Design of Nanoparticle-Based Carriers for Targeted Drug Delivery.

用于靶向药物递送的纳米颗粒载体的设计。