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