Biomimetic Materials to Elucidate the Role of Microenvironment in Glioblastoma Stem Cell Maintenance In Vitro

仿生材料阐明微环境在胶质母细胞瘤干细胞体外维持中的作用

• 批准号: 1604677
• 负责人: Yonghyun Kim
• 金额: $ 42.5万
• 依托单位: University of Alabama Tuscaloosa
• 依托单位国家: 美国
• 项目类别: Standard Grant
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-09-01 至 2020-12-31
• 项目状态: 已结题
• 来源: https://www.nsf.gov/awardsearch/showAward?AWD_ID=1604677&HistoricalAwards=false
• 关键词: Biomimetic; Materials; Elucidate; Role; Microenvironment

#1604677-KimThis project focuses on developing and characterizing hyaluronic acid-based hydrogel 3D matrices as an in vitro test bed for studying glioblastoma stem cells (GSCs or brain tumor initiating cells), which play an important role in tumor formation and tumor recurrence in glioblastoma multiforme (GBM), one of the deadliest forms of human cancer. The matrices will be used to investigate the role of microenvironmental influences, particularly the role of mechanical and chemical signals on GSC phenotype and examine its utility in measuring therapy response. The system has the potential to provide a controllable and tunable environment closely mimicking the in vivo brain. The proposed system could lead to improved therapeutic options for patients (over 22,000/year) suffering from GBM. The system developed could be broadly utilized in understanding the role of microenvironmental signals in multiple types of cancer, particularly those that metastasize to the brain as well as in fundamental studies of neural development. Educational impact is achieved through development of an "Engineering Day" for high school students, providing research opportunities for under-represented female and African-American Students, integration of research related principles into existing courses and providing summer bioengineering workshops for high school students and teachers.This project will combine biomaterials engineering strategies with current understanding of glioblastoma stem cell (GSC; also known as brain tumor initiating cell) biology to design a novel 3D culture system mimicking the native GSC microenvironment that would improve in vitro prediction of therapeutic response by allowing investigation of GSC-matrix interactions. GSCs cell models are superior to established glioblastoma multiforme (GBM) cell lines that are routinely employed in the drug development pipeline. GSCs freshly-derived from GBM patients are known to better recapitulate GBM biology. Though it is well-known that cell behavior is drastically altered when exposed to 3D microenvironments, GSCs are currently mainly cultured in artificial, 2D, and matrix-free environments (i.e., stiff tissue culture polystyrene) that do not appropriately capture the brain microenvironment. Furthermore, softer tissue-like biomaterials afford the ability to present the optimal combination of cues to provide more physiologically relevant environments, which can induce cellular phenotypes typically observed in vivo. For an improved fundamental understanding of microenvironmental influences on GSC phenotype, biomaterials mimicking the in vivo mechanical and chemical cues found in the brain microenvironment must be employed. In the planned studies, the investigators will use biomimetic hyaluronic acid (HA) hydrogels to establish the role of mechanical and chemical signals in maintenance of the GSC phenotype. Furthermore, they will utilize their culture system to quantify therapy response in vitro. Thus the main goal of the project is to create a novel enabling technology that will advance studies of GSC biology and aid future GBM drug development pipelines. GBM is among the deadliest forms of human cancer with an average survival of approximately one year. The proposed work is poised to provide a novel therapeutic evaluation system that can better predict clinical outcomes, thus could lead to improved therapeutic options affecting the lives of over 22,000 individuals per year. The system developed could be broadly utilized in understanding the role of microenvironmental signals in multiple types of cancer, particularly those that metastasize to the brain as well as in fundamental studies of neural development. Outreach activities include: 1) developing "Engineering Day" in high schools of rural Alabama's socioeconomically disadvantaged locality where the students are predominantly African-Americans, 2) providing engineering research opportunities to traditionally under-represented female and African-American students, 3) integrating various biology, materials science, and engineering principles into new and existing undergraduate and graduate level chemical engineering courses, and 4) providing annual summer bioengineering workshops for high school students and teachers.

#1604677-Kim该项目专注于开发和表征基于透明质酸的水凝胶3D基质，作为研究胶质母细胞瘤干细胞（GSC或脑肿瘤起始细胞）的体外试验床，其在多形性胶质母细胞瘤（GBM）的肿瘤形成和肿瘤复发中发挥重要作用，GBM是人类癌症的最致命形式之一。 该矩阵将用于研究微环境影响的作用，特别是机械和化学信号对GSC表型的作用，并检查其在测量治疗反应中的效用。 该系统有可能提供一个可控的和可调的环境密切模仿在体内的大脑。 所提出的系统可以为患有GBM的患者（超过22，000/年）带来更好的治疗选择。 开发的系统可以广泛用于理解微环境信号在多种类型癌症中的作用，特别是那些转移到大脑的癌症以及神经发育的基础研究。 通过为高中生设立“工程日”，为代表性不足的女性和非洲裔美国学生提供研究机会，将研究相关原则纳入现有课程，并为高中生和教师提供暑期生物工程讲习班，实现教育影响。该项目将联合收割机生物材料工程战略与目前对胶质母细胞瘤干细胞的理解相结合GSC（也称为脑肿瘤起始细胞）生物学设计一种新型的3D培养系统，模拟天然GSC微环境，通过研究GSC-基质相互作用，改善治疗反应的体外预测。GSC细胞模型上级于已建立的多形性胶质母细胞瘤（GBM）细胞系，后者通常用于药物开发管道。已知从GBM患者新鲜衍生的GSC更好地概括GBM生物学。虽然众所周知，当暴露于3D微环境时，细胞行为会发生急剧改变，但GSC目前主要在人工、2D和无基质环境（即，硬组织培养聚苯乙烯），无法适当捕获大脑微环境。 此外，较软的组织样生物材料提供了呈现最佳线索组合的能力，以提供更生理相关的环境，这可以诱导通常在体内观察到的细胞表型。 为了更好地了解微环境对GSC表型的影响，必须采用模拟脑微环境中发现的体内机械和化学线索的生物材料。在计划的研究中，研究人员将使用仿生透明质酸（HA）水凝胶来确定机械和化学信号在维持GSC表型中的作用。此外，他们将利用他们的培养系统来量化体外治疗反应。因此，该项目的主要目标是创造一种新的使能技术，以推进GSC生物学的研究，并帮助未来的GBM药物开发管道。GBM是人类癌症中最致命的形式之一，平均生存期约为一年。 这项工作有望提供一种新的治疗评估系统，可以更好地预测临床结果，从而改善治疗选择，每年影响超过22，000人的生活。 开发的系统可以广泛用于理解微环境信号在多种类型癌症中的作用，特别是那些转移到大脑的癌症以及神经发育的基础研究。 外联活动包括：1）在亚拉巴马农村的社会经济弱势地区的高中发展“工程日”，那里的学生主要是非洲裔美国人，2）为传统上代表性不足的女性和非洲裔美国人学生提供工程研究机会，3）将各种生物学、材料科学和工程原理整合到新的和现有的本科和研究生水平的化学工程课程中，4）每年为高中学生和教师提供暑期生物工程工作坊。

项目成果

The impact of temozolomide and lonafarnib on the stemness marker expression of glioblastoma cells in multicellular spheroids

• DOI: 10.1002/btpr.3284
• 发表时间: 2022-06
• 期刊: Biotechnology Progress
• 影响因子: 2.9
• 作者: Pinaki S. Nakod;Raghu Vamsi Kondapaneni;Brandon Edney;Yonghyun Kim;Shreyas S. Rao

Targeting Hyaluronan Interactions for Glioblastoma Stem Cell Therapy

• DOI: 10.1007/s12307-019-00224-2
• 发表时间: 2019-04-01
• 期刊: CANCER MICROENVIRONMENT
• 作者: Hartheimer, Joline S.;Park, Seungjo;Kim, Yonghyun
• 通讯作者: Kim, Yonghyun