Leader cell development and function in Breast Tumor Collective Migration

乳腺肿瘤集体迁移中领导细胞的发育和功能

基本信息

批准号：
10446803
负责人：
Gregory D. Longmore
金额：
$ 52.15万
依托单位：
WASHINGTON UNIVERSITY
依托单位国家：
美国
项目类别：
财政年份：
2022
资助国家：
美国
起止时间：
2022-05-05 至 2027-03-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10446803
关键词：
3-Dimensional Adhesions Affect Basement membrane Biological Process Biomedical Engineering Biophysics Blood Circulation Blood Vessels Breast Cancer Cell Breast Cancer Model Cancer Biology Cancer Etiology Carcinoma Cells Cessation of life Chemicals Collagen Complex Computer Models Computer Simulation Coupling Data Development Disease Environment Event Extracellular Matrix Feedback Fibroblasts Hemidesmosomes Heterogeneity Human Hypoxia Integrins Intercellular Junctions Invaded Lead Lymphatic Malignant Neoplasms Mammary Neoplasms Mechanics Mediating Microfluidic Microchips Microfluidics Molecular Movement Neoplasm Circulating Cells Neoplasm Metastasis Organ Organoids Pathway interactions Primary Neoplasm Production Regulation Signal Transduction Source Stromal Cells Stromal Neoplasm Subgroup Testing Tumor Cell Invasion base biomechanical engineering cell motility chemical property chemokine insight live cell imaging malignant breast neoplasm mechanical properties mechanical signal mechanotransduction migration mouse model neoplastic cell novel polarized cell preservation response single-cell RNA sequencing transcriptome sequencing tumor tumor microenvironment tumor progression

项目摘要

Accumulated evidence in human breast cancer and mouse models of breast cancer have shown that tumor cells invade collectively through the basement membrane (BM) and continue as collective groups to traverse the collagen-rich ECM to access lymphatic and vascular vessels. Rather than single cells, in the circulation clusters of heterogeneous circulating tumor cells (CTCs), that also contain tumor-associated stromal cells such as cancer associated fibroblasts (CAFs), account for >90% of metastases. To move collectively requires coordinated cell–cell and cell–matrix interactions. Hallmarks of collective cell migration include: 1) Cells remain physically and functionally connected such that the integrity of cell–cell junctions are preserved during movement. 2) A subgroup of cells typically defines the leading edge, and thus, the direction of collective migration. These are known as “leader “cells and differ in function from “follower” cells. 3) Collective movement also involves intimate interaction with accessory stromal cells that release polarity-inducing and pro-migratory factors as well as contribute to path finding by physically remodeling the surrounding ECM. Several hypotheses have been proposed to explain cancer leader cell development during collective migration. Yet how these leader cells develop, arrive and define the front edge, then lead directed collective migration, and whether this phenomenon is necessary and sufficient to effect directed collective migration are largely unknown. We have developed novel microfluidic devices in which to study the collective migration of primary breast tumor organoids in response to multiple environmental signals In the present proposal we propose to use primary breast tumor organoids with their inherent cellular heterogeneity to determine how leader cells develop and function, in response to multiple environmental signals, so as to direct collective migration. To do so we propose two specific aims. Specific Aim 1. To determine how K14 leader cells within primary breast tumor organoids polarize to the leading edge and then function to direct collective migration. Specific Aim 2: To understand chemo-mechanical feedback between CAF-based ECM remodeling and leader-based invasion.

在人类乳腺癌和乳腺癌的小鼠模型中积累的证据已显示该肿瘤细胞通过基底膜（BM）集体入侵，并继续作为集体组遍历富含胶原蛋白的ECM以进入淋巴管和血管血管。而不是单个单元，在异质循环肿瘤细胞（CTC）的循环簇，还包含肿瘤相关的基质细胞，例如癌症相关的成纤维细胞（CAF），占转移酶的90％。为了集体移动需要协调的细胞 - 细胞和细胞 - 玛氏体相互作用。标志集体细胞迁移包括：1）细胞在物理和功能上保持连接，使得完整性运动过程中保留了细胞 - 细胞连接的。 2）单元子组通常定义领先边缘，因此是集体迁移的方向。这些被称为“领导者”细胞，功能不同来自“追随者”细胞。 3）集体运动还涉及与辅助基质细胞的紧密相互作用这种释放极性引起的和促迁移的因素，并通过物理上有助于发现路径重塑周围的ECM。已经提出了几种假设来解释集体期间癌症领导者细胞的发展迁移。然而，这些领导者细胞如何发展，到达和定义前边缘，然后引导指向集体迁移，以及这种现象是否必要且足以实现定向的集体迁移在很大程度上未知。我们已经开发了新型的微流体设备来研究集体响应多个环境信号的原发性乳腺肿瘤类器官的迁移在目前的建议中，我们建议使用及其遗传细胞的原发性乳腺肿瘤器官响应多个环境的异质性以确定领导者的发展和功能信号，以指导集体迁移。为此，我们提出了两个具体目标。特定目标1。确定原发性乳腺肿瘤类器官中的K14领导细胞如何偏向前缘，然后指导集体迁移的功能。特定目的2：了解化学机械反馈基于CAF的ECM改建和基于领导者的入侵。