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

• 批准号: 10618305
• 负责人: Gregory D. Longmore
• 金额: $ 49.74万
• 依托单位: WASHINGTON UNIVERSITY
• 依托单位国家: 美国
• 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/10618305
• 关键词: 3-Dimensional; Adhesions; Affect; Basement membrane; Biological Process; Biomedical Engineering; Biophysics; Blood Vessels; Breast Cancer Cell; Breast Cancer Model; Cancer Biology; Cancer Etiology; Carcinoma; Cells; Cessation of life; Chemicals; Circulation; 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; 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; treatment response; tumor; tumor microenvironment; tumor progression

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.

在人类乳腺癌和小鼠乳腺癌模型中积累的证据表明， 肿瘤细胞通过基底膜（BM）集体侵入并作为集体群体继续存在 穿过富含胶原的细胞外基质进入淋巴管和血管。而不是单个细胞，在 异质性循环肿瘤细胞（CTC）的循环簇，其还含有肿瘤相关的 基质细胞如癌相关成纤维细胞（CAF）占转移灶的>90%。 集体运动需要协调的细胞-细胞和细胞-基质相互作用。的标志 集体的细胞迁移包括：1）细胞保持物理和功能连接，使得细胞的完整性和完整性不受影响。 在运动过程中细胞间的连接得以保留。2)单元格的子组通常定义前导 边缘，因此，集体迁移的方向。这些细胞被称为“领导者”细胞，功能不同 从“追随者”细胞。3)集体运动还涉及与辅助基质细胞的密切相互作用 释放极性诱导因子和促迁移因子， 重塑周围的细胞外基质 已经提出了几种假说来解释集体癌症中的领导细胞的发展。 迁移然而，这些领导细胞如何发展，到达并确定前沿，然后领导有针对性的集体 移民，以及这种现象是否是必要的和充分的影响定向集体移民 大部分都是未知的。我们已经开发了新的微流体设备，在其中研究集体 原发性乳腺肿瘤类器官响应多种环境信号的迁移 在本提案中，我们建议使用具有其固有细胞的原发性乳腺肿瘤类器官。 异质性，以确定领导细胞如何发展和功能，以响应多种环境 #21453;的信号，引导集体迁徙。为此，我们提出两个具体目标。具体目标1。到 确定原发性乳腺肿瘤类器官内的K14前导细胞如何转移到前沿， 引导集体移民。具体目标2：了解化学机械反馈之间 基于CAF的ECM重塑和基于领导者的入侵。