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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：
9883630
负责人：
Brendan A. Harley
金额：
$ 37.98万
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/9883630
关键词：
Acute Address Affect Animals Benchmarking Biocompatible Materials Biological Assay Biological Markers Biomimetics Biophysics Brain Cell Line Cells Clinical Consumption Cues Diffuse Engineering Epidermal Growth Factor Receptor Event Face Future Generations Genomics Glioblastoma Glioma Goals Gold Growth Heterogeneity Hydrogels Image Immune In Vitro Libraries Malignant Neoplasms Malignant neoplasm of brain Maps Microfluidics Modeling Molecular Analysis Monitor Mutation Neoplasm Metastasis Optics 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 immortalization cell type clinical biomarkers clinical phenotype clinically relevant defined contribution design in vivo in vivo Model individual patient innovation insight malignant phenotype miniaturize molecular phenotype mortality next generation novel strategies patient variability personalized medicine point of care precision medicine preservation public health relevance 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迅速扩散，因此有必要研究发生在肿瘤边缘的现象。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患者来源的生物干细胞而不是通用细胞系是至关重要的。该领域的一个主要瓶颈是目前尚不清楚跨越GBM肿瘤的生物物理和生物分子信号的组合如何影响恶性表型和治疗反应。能够复制天然肿瘤微环境的调控元素的空间图案化生物材料是必不可少的。我们开发了一种微流体形成技术，以创建光学半透明工程胶质瘤生物材料库，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图案。我们能够通过转录、分泌和成像指标对EG离散亚区的细胞进行多路分析，将细胞反应映射为局部微环境的函数。虽然利用永生化细胞系成功地解决了与临床相关的现象，但临床上迫切需要能够从患者来源的生物标本中收集类似信息的护理点工具。这项应用的主要目的是展示一种仿生组织工程方法，利用患者体内来源的生物旋毛虫研究潜在的表型机制。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。目的2将确定血管周围信号对侵袭性表型的贡献。AIM 3将使用工程化胶质瘤通过与临床表型的定量基准来解决原位和异位异种移植瘤之间的不一致性。基因工程的胶质瘤生物材料提供了洞察大脑皮层微环境的空间和时间方面的潜力，而目前的实验方法是不可能的。我们使用可扩展的微流控平台，以及通过传统和新一代分子分析工具对GBM细胞进行多路评估，大大减少了所需患者生物样品的大小，加快了分析速度，同时保留了询问稀有细胞亚群(如胶质瘤癌症干细胞)的能力。工程化的胶质瘤生物材料有可能成为

项目成果

期刊论文数量（12）

专著数量（0）

科研奖励数量（0）

会议论文数量（0）

专利数量（0）

Progress in mimicking brain microenvironments to understand and treat neurological disorders.

DOI：
10.1063/5.0043338
发表时间：
2021-06
期刊：
APL bioengineering
影响因子：
6
作者：
Ngo MT;Harley BAC
通讯作者：
Harley BAC

Three-dimensional hydrogel culture systems support growth and determination of chemosensitivity of feline sarcoma and carcinoma cell lines.

三维水凝胶培养系统支持猫肉瘤和癌细胞系的生长和化学敏感性的测定。

DOI：
10.2460/ajvr.21.10.0157
发表时间：
2022
期刊：
American journal of veterinary research
影响因子：
1
作者：
Cavalcanti,JacquelineVJ;Selting,KimberlyA;Ngo,MaiT;TranHoang,ChristineK;Schaeffer,DavidJ;Fan,TimothyM;Harley,BrendanAC;Phillips,Heidi
通讯作者：
Phillips,Heidi

The Influence of Hyaluronic Acid and Glioblastoma Cell Coculture on the Formation of Endothelial Cell Networks in Gelatin Hydrogels.

透明质酸和胶质母细胞瘤细胞共培养对明胶水凝胶中内皮细胞网络形成的影响。

DOI：
10.1002/adhm.201700687
发表时间：
2017
期刊：
Advanced healthcare materials
影响因子：
10
作者：
Ngo,MaiT;Harley,BrendanA
通讯作者：
Harley,BrendanA

The Feasibility of Encapsulated Embryonic Medullary Reticular Cells to Grow and Differentiate Into Neurons in Functionalized Gelatin-Based Hydrogels.

封装的胚胎髓质网状细胞在功能化明胶基水凝胶中生长和分化为神经元的可行性。

DOI：
10.3389/fmats.2018.00040
发表时间：
2018
期刊：
Frontiers in materials
影响因子：
3.2
作者：
Magariños,AnaM;Pedron,Sara;Creixell,Marc;Kilinc,Murat;Tabansky,Inna;Pfaff,DonaldW;Harley,BrendanAC
通讯作者：
Harley,BrendanAC

Spatially graded hydrogels for preclinical testing of glioblastoma anticancer therapeutics.