Tissue-Engineered Models of Glioblastoma for Evaluating Treatment Response

用于评估治疗反应的胶质母细胞瘤组织工程模型

• 批准号: 10579031
• 负责人: Stephanie Kristin Seidlits
• 金额: $ 51.99万
• 依托单位: UNIVERSITY OF TEXAS AT AUSTIN
• 依托单位国家: 美国
• 财政年份: 2020
• 资助国家: 美国
• 起止时间: 2020-02-13 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10579031
• 关键词: 3-Dimensional; Address; Affect; Atomic Force Microscopy; Behavior; Biochemical; Biocompatible Materials; Biomechanics; Biomedical Engineering; Blood Vessels; Brain; Cell Culture Techniques; Cell Survival; Cells; Chemicals; Chemotherapy and/or radiation; Clinical; Coculture Techniques; Coupling; Cues; Development; Endothelial Cells; Environment; Event; Excision; Exhibits; Experimental Models; Exposure to; Extracellular Matrix; Glioblastoma; Glioma; Heterogeneity; Individual; Infiltration; Invaded; Knowledge; Malignant neoplasm of brain; Measures; Mechanics; Modeling; Operative Surgical Procedures; Patients; Phenotype; Population Heterogeneity; Primary Neoplasm; Property; Recurrence; Recurrent tumor; Reporting; Resistance; Role; Seeds; Site; Stimulus; Time; Tissue Engineering; Tissues; Tumor Cell Invasion; Tumor Cell Migration; Xenograft procedure; base; brain tissue; cancer cell; cell behavior; cell motility; chemical property; combat; effective therapy; experimental study; innovation; insight; mechanical properties; mechanical signal; migration; neoplastic cell; neuro-oncology; new therapeutic target; response; single-cell RNA sequencing; stem; targeted treatment; therapy resistant; three dimensional cell culture; transcriptomics; treatment response; tumor; tumor microenvironment; tumor progression; tumor xenograft; virtual

Glioblastoma (GBM) is a uniformly fatal brain cancer with poor response to treatment and virtually inevitable recurrence. GBM tumors do not metastasize. Instead, they aggressively infiltrate the brain. Tumor borders are highly vascularized by microvessels that serve as key niche environments promoting GBM cell survival, treatment resistance and migration. Currently, it is believed that a subpopulation of treatment-resistant, stem- like GBM cells (GSCs) migrate away from primary tumors — remaining in close contact with local microvessels — and seed recurrent tumors — which are enriched in GSCs. However, the mechanisms underlying the influence of the microvessel niche on GBM cell migration away from primary tumors, leading to recurrence, remain largely unknown. To address this gap in knowledge, the proposed studies will investigate 1) the role of specific cues in the tumor microenvironment on the migratory phenotype of GBM cells and 2) how these cues differentially affect distinct subpopulations of cells within heterogeneous tumors, including GSCs. Our fundamental hypothesis is that the microenvironment surrounding tumor microvessels promotes GBM progression through both mechanical and chemical means. Aim 1 will investigate effects of mechanical cues and Aim 2 effects of biochemical cues present in the microvessel niche on migratory phenotype of GBM. To do this, we will use an innovative, tissue- engineered platform for 3D culture of patient-derived GBM cells to quantify how specific features of the microenvironment affect migratory behavior. We propose to modularly tune mechanical and chemical properties of culture platforms to characterize their independent effects on migratory phenotype of GBM. For some experiments, platforms will be constructed with an interface between defined microenvironments through which GBM cells can migrate, enabling separation of migratory and non-migratory cells for downstream analysis and providing information about how subpopulations of cells within a single tumor, such as GSCs, may respond differentially to microenvironmental cues. As treatment resistance, invasion and recurrence are inter-related events, we will investigate how exposure to routine clinical therapies may alter migratory responses of GBM to microenvironmental cues. Using single-cell RNA sequencing, we will investigate the mechanisms underlying responses to specific features of the microvessel niche. Collectively, the proposed studies will make significant strides towards our understanding of how interactions of GBM with the microvessel niche promote tumor recurrence by characterizing: 1) biomechanical properties of GBM tumors and microvessels (Aim 1), 2) migratory response of GBM cells to biochemical and biomechanical cues (Aims 1 and 2) and 3) mechanisms governing the migratory responses to biochemical and biomechanical cues (Aims 1 and 2). In the long term, we expect these insights will lead to the development of new therapies targeting GBM recurrence. !

胶质母细胞瘤（GBM）是一种致命的脑癌，治疗效果差，几乎不可避免 复发GBM肿瘤不转移。相反，他们积极地渗透到大脑。肿瘤边界 由微血管高度血管化，微血管作为促进GBM细胞存活的关键生态位环境， 治疗阻力和迁移。目前，人们认为，一个耐药的、干细胞- 类似GBM细胞（GSC）从原发性肿瘤中迁移出来-与局部微血管保持密切接触 - 和种子复发肿瘤-这是富含GSC。然而，影响的机制 GBM细胞迁移远离原发性肿瘤，导致复发的微血管龛， 未知为了解决这一知识缺口，拟议的研究将调查1）特定线索在 肿瘤微环境对GBM细胞迁移表型的影响，以及2）这些线索如何差异化地影响 异质性肿瘤内不同的细胞亚群，包括GSC。我们的基本假设是 肿瘤微血管周围的微环境通过两种机制促进GBM进展， 化学手段。目标1将研究机械线索的影响，目标2将研究生化线索的影响 存在于GBM迁移表型的微血管龛中。为了做到这一点，我们将使用一种创新的，组织- 用于患者来源的GBM细胞的3D培养的工程化平台，以量化GBM细胞的特定特征如何影响细胞的生长。 微环境影响迁移行为。我们建议模块化调整机械和化学性能 的培养平台，以表征其对GBM迁移表型的独立影响。对于一些 实验中，平台将被构建为具有定义的微环境之间的接口， GBM细胞可以迁移，使得能够分离迁移和非迁移细胞用于下游分析， 提供关于单个肿瘤内的细胞亚群（如GSC）如何响应的信息， 微环境线索的差异。由于耐药、侵袭和复发是相互关联的 事件，我们将研究如何暴露于常规临床治疗可能会改变GBM的迁移反应， 微环境线索使用单细胞RNA测序，我们将研究潜在的机制， 对微血管生态位的特定特征的反应。总的来说，拟议的研究将使 我们对GBM与微血管龛的相互作用如何促进肿瘤的理解取得了进展 通过表征复发：1）GBM肿瘤和微血管的生物力学特性（目的1），2）迁移 GBM细胞对生物化学和生物力学线索的反应（目的1和2）和3）控制GBM细胞的机制 对生物化学和生物力学线索的迁移反应（目标1和2）。从长远来看，我们预计 这些见解将导致针对GBM复发的新疗法的开发。 !