Investigating Pathophysiology of Glioma Stem Cells in 3D Bioprinted Vascularized Glioblastoma Model

研究 3D 生物打印血管化胶质母细胞瘤模型中胶质瘤干细胞的病理生理学

• 批准号: 10373269
• 负责人: Irtisha Singh
• 金额: $ 21.85万
• 依托单位: TEXAS A&M UNIVERSITY HEALTH SCIENCE CTR
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-01-01 至 2023-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10373269
• 关键词: 3-Dimensional; Ablation; Adult; Animal Model; Area; Astrocytes; Biochemical; Biocompatible Materials; Biological Models; Biology; Biomedical Engineering; Biophysics; Blood Vessels; Brain; Brain Neoplasms; Cell Differentiation process; Cells; Collaborations; Cues; Dependence; Development; Drug Screening; Ecology; Endothelial Cells; Engineering; Environment; Epigenetic Process; Equilibrium; Exhibits; Extracellular Matrix; Failure; Functional disorder; Gene Expression; Genetic; Glioblastoma; Glioma; Goals; Immune; Immune system; Implant; In Vitro; Letters; Maintenance; Malignant Neoplasms; Modeling; Molecular; Molecular Genetics; National Institute of Neurological Disorders and Stroke; Nature; Neoplasms in Vascular Tissue; Normal Cell; Organoids; Pathologic; Patients; Pericytes; Physiological; Pre-Clinical Model; Primary Brain Neoplasms; Publications; Radiation therapy; Regulation; Research Design; Resistance; Role; Structure; Survival Rate; System; Therapeutic; Tissues; bioink; bioprinting; body system; cell type; clinically relevant; density; design; drug development; high-throughput drug screening; human disease; in vitro Model; in vivo; innovation; mouse model; neoplastic cell; nerve stem cell; novel therapeutics; patient derived xenograft model; pre-clinical; precision medicine; programs; relating to nervous system; self-renewal; stem cells; stem-like cell; stemness; therapy development; therapy resistant; three-dimensional modeling; tool; tumor; tumor growth; tumor microenvironment; tumorigenic

SUMMARY Glioblastoma multiforme (GBM) is the most lethal primary brain tumor in adults with a 5-year survival rate of less than 5%. GBMs are highly vascular and lethal brain tumors that display cellular hierarchies containing self- renewing and radiotherapy resistant tumorigenic glioma stem cells (GSCs). Understanding of the molecular regulation of GSCs in its native environment is critical for drug development. The available in vitro models suffer from the momentous hurdle of lack of functional blood vessels. Vasculature is not only essential for keeping the tumor alive but also creating a tumor microenvironment that balances the dynamics of GSCs, enabling self-renewal and differentiation. Therefore, there is a significant need for a preclinical tumor model to investigate the progression and the therapeutic resistance nature of GBM tumor, and thereby aid in drug development for the treatment of GBM. The primary goal of this exploratory (R21) proposal is to (a) develop clinically-relevant bioengineered 3D vascularized GBM organoid models and (b) utilize them to interrogate GBM pathobiology. Specifically, 3D bioprinting approach will be used to design perfusable vascular networks with embedded GSC organoids in a brain-like extracellular matrix. This printed structure will have the potential to provide physiologically similar biophysical and biochemical microenvironment with perivascular niches to facilitate maintenance of stemness cues as well as transformation of GSCs into differentiated glioma cells. As ablation of GSCs represents a potential therapeutic approach for treatment of GBM, these bioengineered GBM models can be utilized to understand the molecular regulation of GSCs in a microenvironment mimicking its native surroundings. It is envisioned that these 3D bioprinted vascularized GBM models will not only serve as a powerful platform to study GBM but will serve as invaluable tools for drug screens for precision medicine.

摘要 多形性胶质母细胞瘤(GBM)是成人最致命的原发脑肿瘤，5年生存率为 不到5%。基底节细胞瘤是一种高度血管性和致命性的脑肿瘤，其细胞层次结构包含自身 再生和抗放射治疗的成瘤性胶质瘤干细胞(GSCs)。对分子的理解 对GSCs在其本土环境中的调节对药物开发至关重要。可利用的体外模型 遭受缺乏功能血管的重大障碍。血管系统不仅对 保持肿瘤存活，但也创造了一个平衡GSCs动态的肿瘤微环境， 实现自我更新和差异化。因此，临床前肿瘤模型非常有必要 探讨基底膜肿瘤的进展和耐药特性，从而为药物治疗提供帮助 基底膜的治疗进展。此探索性(R21)提案的主要目标是(A)开发 临床相关的生物工程3D血管基底膜器官模型和(B)利用它们询问 GBM病理生物学。具体来说，将使用3D生物打印方法来设计可灌流的血管网络 在类脑细胞外基质中嵌入GSC有机化合物。这种印刷结构将具有潜在的 为生理上相似的生物物理和生化微环境提供血管周围的利基环境 促进干性线索的维持以及将GSCs转化为分化的胶质瘤细胞。AS GSCs的消融是治疗GBM的一种潜在的治疗方法，这些生物工程GBM 模型可以用来理解GSCs在模拟其微环境中的分子调控 原生环境。据设想，这些3D生物打印的血管化GBM模型不仅将用作 研究GBM的强大平台，但将成为精准医学药物筛选的宝贵工具。