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

基本信息

批准号：
9888360
负责人：
Celeste M Nelson
金额：
$ 74.9万
依托单位：
BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
依托单位国家：
美国
项目类别：
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/9888360
关键词：
3-Dimensional Behavior Biochemical Biocompatible Materials Biopsy Blood Vessels Blood capillaries Cancer Model Candidate Disease Gene Carcinoma Cell Culture Techniques Cells Chemicals Clinical Data Correlations Developmental Biology Disease Engineering Expression Profiling Extracellular Matrix Gene Expression Profiling Genes Genetic Genetic study Geometry Goals Harvest Human Hydrogels In Vitro Intercellular Fluid Interruption Invaded Laboratory Research Lesion Lymphatic Malignant Neoplasms Mammary Neoplasms Maps Mechanical Stress Mechanics Methods Modeling Mosaicism Mutation Neoplasms in Vascular Tissue Normal Cell Organ Organizational Models Oxygen Pathology Patients Perfusion Physiological Play Process Role Route Sampling Signal Transduction Stress System Techniques Technology Testing Tissue Engineering Tissues Tumor Biology Tumor Cell Invasion Tumor Escape Tumor Tissue Tumor stage Work Xenograft procedure anticancer research cancer cell cancer type cell behavior cell transformation chemical genetics density design genetic signature human model in vitro Model in vivo interstitial interstitial cell lymphatic drainage lymphatic vessel malignant breast neoplasm neoplastic cell non-invasive imaging pressure scaffold temporal measurement tumor tumor progression

项目摘要

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对肿瘤及其关键方面的模块化控制来提供更强大的系统微环境，例如血管密度或间质压力。这项合作研究旨在开发并应用体外工程血管化肿瘤的新方法，其中细胞、物理和遗传肿瘤的组成及其微环境可以以高空间和时间分辨率进行控制。合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（Radisky）病理学（纳萨尔）。我们在过去十五年中一直在开发的核心支持技术是使用三维 (3D) 微图案细胞外基质水凝胶作为引导 3D 的支架工程组织的组织。具体来说，拟议的工作将创造微型人类乳房含有灌注毛细血管和引流淋巴管的肿瘤，为肿瘤细胞逃逸提供了途径并能够捕获这些细胞以进行下游表达谱分析。间隙应力和生化将分别通过非侵入性成像和间质液的重复采样来分析成分，以提供与肿瘤细胞行为相关的纵向数据。这项工作还将创造血管化胶原基质可以接受人类乳腺肿瘤活检作为体外“患者来源的异种移植物”，用于发现有利于肿瘤侵袭和逃逸的候选突变；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，这项工作将传播这些微型组织工程技术可用于癌症研究实验室以适应其他类型癌症和肿瘤细胞行为。