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Biomimetic hydrogel niches to study the malignant phenotype of glioblastoma multiforme

仿生水凝胶利基研究多形性胶质母细胞瘤的恶性表型

基本信息

批准号：
9106977
负责人：
Brendan A. Harley
金额：
$ 35.81万
依托单位：
UNIVERSITY OF ILLINOIS AT URBANA-CHAMPAIGN
依托单位国家：
美国
项目类别：
财政年份：
2016
资助国家：
美国
起止时间：
2016-03-17 至 2021-02-28
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/9106977
关键词：
Acute Address Affect Animals Benchmarking Biocompatible Materials Biological Assay Biological Markers Biomimetics Brain Cell Line Cells Clinical Cues Engineering Epidermal Growth Factor Receptor Event Face Future Generations Generic Drugs Genomics Glioblastoma Glioma Goals Gold Growth Health Heterogeneity Hydrogels Image Immune In Vitro Libraries Malignant Neoplasms Malignant neoplasm of brain Maps Microfluidics Modeling Molecular Analysis Monitor Mutation Neoplasm Metastasis Organoids Patient Care Patients Pattern Phenotype Population Process Regulatory Element Resolution Scientist Series Shapes Signal Transduction Specimen Speed Techniques Testing Time Tissue Engineering Tissues Treatment Efficacy Xenograft Model anticancer research cancer stem cell cancer therapy cell type clinical biomarkers clinical phenotype clinically relevant defined contribution design immortalized cell in vivo in vivo Model individual patient innovation insight malignant phenotype miniaturize molecular phenotype mortality next generation novel strategies personalized medicine point of care precision medicine response tissue tropism tool transcriptomics treatment response tumor tumor growth tumor microenvironment tumor xenograft

项目摘要

DESCRIPTION: Glioblastoma multiforme (GBM) is the most common, aggressive, and deadly form of brain cancer GBM spreads rapidly and diffusely via distinct invasive processes, making it essential to investigate phenomena occurring at the tumor margins. And given the number of independent genomic mutations associated with GBM, it is critical to develop biomimetic tissue engineering approaches to directly study patient-derived biospecimens rather than generic cell lines. A major bottleneck in the field is that it remains unclear how combinations of biophysical and biomolecular signals that exist in close spatial and temporal order across the GBM tumor affect malignant phenotype and response to therapy. Spatially-patterned biomaterials capable of replicating regulatory elements of the native tumor microenvironment such as the margins are essential. We have developed a microfluidic forming technique to create libraries of optically-translucent engineered glioma biomaterials containing overlapping patterns of cell, matrix, and biomolecular cues inspired by the GBM margins. We are able to map cell response as a function of local microenvironment via multiplexed analyses of cells from discrete sub-regions of the EG via transcriptomic, secretomic, and imaging metrics. While successful for resolving clinically-relevant phenomena using immortalized cell lines, there is an acute clinical need for point-of-care tools able to gather similar information from patient-derived biospecimens. The primary objective of this application is to demonstrate a biomimetic tissue engineering approach to investigate mechanisms underlying phenotype using patient-derived biospecimens ex vivo. Aim 1 will dissect how overlapping patterns of tumor margin-inspired signals shape malignant phenotype. Aim 2 will define the contribution of perivascular signals on invasive phenotype. Aim 3 will employ engineered gliomas to resolve discordances between orthotopic and heterotopic xenograft tumors via quantitative benchmarking against clinical phenotype. Engineered glioma biomaterials offer the potential for insight regarding spatial and temporal aspects of the GBM microenvironment in ways not possible with current experimental approaches. Our use of a scalable microfluidic platform as well as multiplexed assessment of GBM cells via conventional and next generation molecular analysis tools greatly reduces the size of the required patient biospecimen, accelerates the speed of analysis, and yet preserves the capability of interrogating rare cell subpopulations such as glioma cancer stem cells. Engineered glioma biomaterials have the potential to b

描述：多形性胶质母细胞瘤 (GBM) 是最常见、最具侵袭性和致命性的脑癌，GBM 通过不同的侵袭过程快速、广泛地扩散，因此有必要研究肿瘤边缘发生的现象。考虑到与 GBM 相关的独立基因组突变的数量，开发仿生组织工程方法来直接研究源自患者的生物样本而不是通用细胞系至关重要。该领域的一个主要瓶颈是，目前尚不清楚 GBM 肿瘤中以紧密的空间和时间顺序存在的生物物理和生物分子信号的组合如何影响恶性表型和对治疗的反应。能够复制天然肿瘤微环境（例如边缘）的调节元件的空间图案生物材料是至关重要的。我们开发了一种微流体成型技术来创建光学半透明的工程神经胶质瘤生物材料库，其中包含受 GBM 边缘启发的细胞、基质和生物分子线索的重叠模式。我们能够通过转录组、分泌组和成像指标对来自 EG 离散子区域的细胞进行多重分析，将细胞反应绘制为局部微环境的函数。虽然使用永生化细胞系成功解决了临床相关现象，但临床迫切需要能够从患者来源的生物样本中收集类似信息的护理工具。该应用的主要目的是展示一种仿生组织工程方法，利用来自患者的离体生物样本来研究表型背后的机制。目标 1 将剖析肿瘤边缘激发信号的重叠模式如何塑造恶性表型。目标 2 将定义血管周围信号对侵袭表型的贡献。目标 3 将利用工程神经胶质瘤，通过针对临床表型的定量基准来解决原位和异位异种移植肿瘤之间的不一致。工程神经胶质瘤生物材料提供了以当前实验方法无法实现的方式洞察 GBM 微环境的空间和时间方面的潜力。我们使用可扩展的微流体平台以及通过传统和下一代分子分析工具对 GBM 细胞进行多重评估，大大减少了所需患者生物样本的大小，加快了分析速度，同时保留了询问罕见细胞亚群（例如神经胶质瘤干细胞）的能力。工程神经胶质瘤生物材料有潜力