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: 10545037
• 负责人: Irtisha Singh
• 金额: $ 18.48万
• 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 2024-12-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10545037
• 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; Cells; Collaborations; Cues; Dependence; Development; Drug Screening; Ecology; Endothelial Cells; Engineering; Environment; Epigenetic Process; 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; Normal Cell; Organoids; Pathologic; Patients; Pericytes; Physiological; Pre-Clinical Model; Primary Brain Neoplasms; Printing; Proliferating; Publications; Radiation therapy; Regulation; Research; Role; Structure; Survival Rate; System; Therapeutic; Tissues; Vascularization; 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; neural; novel therapeutics; patient derived xenograft model; pre-clinical; precision medicine; programs; 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.

总结 多形性胶质母细胞瘤（GBM）是成人中最致命的原发性脑肿瘤，5年生存率为 不到5%。GBM是高度血管化和致命的脑肿瘤，其显示包含自身免疫的细胞层次结构。 更新和放射治疗抗性的致瘤性胶质瘤干细胞（GSC）。对分子的理解 GSC在其天然环境中的调节对于药物开发至关重要。可用的体外模型 因为缺乏功能性血管而遭受重大障碍。血管系统不仅对 保持肿瘤存活，但也创造了一个平衡GSC动力学的肿瘤微环境， 使自我更新和分化成为可能。因此，非常需要临床前肿瘤模型， 研究GBM肿瘤的进展和治疗抗性性质，从而有助于药物治疗。 用于治疗GBM。本探索性（R21）提案的主要目标是：（a）开发 临床相关的生物工程3D血管化GBM类器官模型，和（B）利用它们来询问 GBM病理生物学。具体而言，3D生物打印方法将用于设计可灌注的血管网络 在脑样细胞外基质中嵌入GSC类器官。这种印刷结构将有可能 提供具有血管周围小生境的生理学上相似的生物物理和生物化学微环境， 促进干性线索的维持以及GSC转化为分化的神经胶质瘤细胞。作为 GSC的消融代表了用于治疗GBM的潜在治疗方法，这些生物工程GBM 模型可用于理解在模拟其微环境中GSC的分子调控。 原生环境据设想，这些3D生物打印的血管化GBM模型将不仅用作 强大的平台来研究GBM，但将作为药物筛选的宝贵工具，为精准医疗。