Engineered invasive human breast tumors with integrated capillaries and lymphatics

具有集成毛细血管和淋巴管的工程侵袭性人类乳腺肿瘤

• 批准号: 9912555
• 负责人: Celeste M Nelson
• 金额: $ 4.51万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2017
• 资助国家: 美国
• 起止时间: 2017-04-01 至 2022-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9912555
• 关键词: 3-Dimensional; Biochemical; Biocompatible Materials; Biopsy; Blood Vessels; Blood capillaries; Cells; Clinical; Data Correlations; Developmental Biology; Dimensions; Disease; Engineering; Expression Profiling; Extracellular Matrix; Genetic; Human; Hydrogels; In Vitro; Intercellular Fluid; Interruption; Invaded; Laboratory Research; Lymphatic; Malignant Neoplasms; Mammary Neoplasms; Mechanics; Methods; Modeling; Mutation; Neoplasms in Vascular Tissue; Organizational Models; Pathology; Patients; Physiological; Route; Sampling; Signal Transduction; Stress; System; Techniques; Technology; Testing; Tissue Engineering; Tumor Biology; Tumor Cell Invasion; Tumor Escape; Work; Xenograft procedure; anticancer research; cancer cell; cancer type; cell behavior; density; human model; in vitro Model; in vivo; interstitial; neoplastic cell; non-invasive imaging; pressure; scaffold; temporal measurement; tumor; tumor progression

PROJECT SUMMARY Current in vivo and in vitro models of human cancer remain limited in their ability to replicate progression to invasive disease in an easily accessible and physiologically relevant format. Tissue-engineered tumors may provide a more powerful system by enabling modular control over key aspects of a tumor and its microenvironment, such as vascular density or interstitial pressure. This collaborative study seeks to develop and apply new methods of engineering vascularized tumors in vitro, in which the cellular, physical, and genetic composition of the tumor and its microenvironment can be controlled with high spatial and temporal resolution. The collaborative team consists of experts in biomaterials and tissue engineering (Tien), quantitative developmental and tumor biology (Nelson), mechanics (Ekinci), and clinical tumor biology (Radisky) and pathology (Nassar). The core enabling technology, which we have been developing over the past fifteen years, is the use of three-dimensional (3D) micropatterned extracellular matrix hydrogels as scaffolds for directing the 3D organization of engineered tissues. Specifically, the proposed work will create microscale human breast tumors that contain perfused capillaries and draining lymphatics, which provide routes for tumor cell escape and enable the capture of those cells for downstream expression profiling. Interstitial stresses and biochemical composition will be analyzed by non-invasive imaging and repeated sampling of interstitial fluid, respectively, to provide longitudinal data for correlation with tumor cell behavior. This work will also create vascularized collagenous stroma that can accept human breast tumor biopsies as in vitro "patient-derived xenografts", for the discovery of candidate mutations that favor tumor invasion and escape; these mutations will then be tested in hypothesis-driven analyses using the engineered breast tumors. More broadly, this work will disseminate these microscale tissue engineering technologies to cancer research laboratories for adaptation to other types of cancers and tumor cell behaviors.

项目概要 目前的人类癌症体内和体外模型的复制能力仍然有限 以易于获取且生理相关的形式进展为侵袭性疾病。 组织工程肿瘤可以通过模块化控制提供更强大的系统 肿瘤及其微环境的关键方面，例如血管密度或间质 压力。这项合作研究旨在开发和应用新的工程方法 体外血管化肿瘤，其中肿瘤的细胞、物理和遗传组成 其微环境可以以高时空分辨率进行控制。这 协作团队由生物材料和组织工程专家（Tien）、定量专家组成 发育和肿瘤生物学（Nelson）、力学（Ekinci）和临床肿瘤生物学 （拉迪斯基）和病理学（纳萨尔）。我们一直致力于的核心使能技术 过去十五年的发展，是使用三维（3D）微图案 细胞外基质水凝胶作为指导工程 3D 组织的支架 组织。具体来说，拟议的工作将创建微型人类乳腺肿瘤，其中包含 灌注毛细血管和引流淋巴管，为肿瘤细胞逃逸提供途径 并能够捕获这些细胞以进行下游表达谱分析。间隙应力 生化成分将通过非侵入性成像和重复采样进行分析 分别提供与肿瘤细胞相关的纵向数据 行为。这项工作还将创造出可以接受人类的血管化胶原基质 乳腺肿瘤活检作为体外“患者来源的异种移植物”，用于发现候选物 有利于肿瘤侵袭和逃逸的突变；然后将测试这些突变 使用工程乳腺肿瘤进行假设驱动的分析。更广泛地说，这项工作将 将这些微型组织工程技术传播到癌症研究实验室 用于适应其他类型的癌症和肿瘤细胞行为。