A novel photopatterning-based paradigm for the study of 3D tumor infiltration

用于研究 3D 肿瘤浸润的新型基于光图案的范例

• 批准号: 8457915
• 负责人: Andrew Rape
• 金额: $ 4.71万
• 依托单位: UNIVERSITY OF CALIFORNIA BERKELEY
• 依托单位国家: 美国
• 财政年份: 2013
• 资助国家: 美国
• 起止时间: 2013-02-01 至 2016-01-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/8457915
• 关键词: Address; Adhesives; Aggressive Clinical Course; Biochemistry; Biocompatible Materials; Biological; Biological Models; Blood Vessels; Brain; Brain Neoplasms; Cells; Chemistry; Clinical; Connective Tissue; Cues; Diagnosis; Disease; Environment; Excision; Extracellular Matrix; Fellowship; Fibronectins; Florida; Focal Adhesion Kinase 1; Glioblastoma; Glioma; Goals; Human; Hyaluronic Acid; Hydrogels; In Vitro; Infiltration; Knowledge; Laminin; Life; Ligands; Malignant Neoplasms; Malignant neoplasm of brain; Mechanics; Modeling; Molecular; Neoplasm Metastasis; Pattern; Peptides; Photochemistry; Play; Procedures; Process; Property; Proteins; Recurrence; Research; Resected; Role; Signal Pathway; Signal Transduction; Structure; System; Testing; Time; Tissues; Tumor Cell Invasion; Tumor Stem Cells; Work; base; brain tissue; cell motility; cellular imaging; common treatment; crosslink; density; design; in vitro Model; innovation; insight; migration; mimetics; mortality; neoplastic cell; novel; overexpression; public health relevance; scaffold; stem cell biology; therapeutic target; tool; tumor; two-dimensional; two-photon; white matter

DESCRIPTION (provided by applicant): Glioblastoma multiforme (GBM) is the most common and deadly form of brain cancer found in humans. The median time to tumor recurrence after resection is just 6.9 months after common treatment; the median survival time from diagnosis is just 1-2 years. Its uncommonly aggressive migration away from the host tumor is likely responsible for the inability to completely surgically resect the tumor, rendering a curative treatment currently out of reach. The broad goals of this project are to develop more in depth understanding of GBM migration away from the host tumor. It is widely recognized that GBM dissemination occurs along defined "tracks" in the brain, including vasculature and white matter tracts, but this phenomenon is poorly understood. The spatial inhomogeneities presented by these tracks - including, stiffness and ligand inhogenieties - may help to guide cells away from the host tumor. In this proposal, we seek to create an in vitro model system to replicate the spatial inhomogoneities present in tumors and ask whether spatial stiffness and ligand inhomogeneities can enhance GBM cell migration. To accomplish this, this proposal has three specific aims. Aim 1 is to develop a three-dimensional hyaluronic acid platform with orthogonal control of matrix stiffness and ligand attachment. We will use two- photon activation of orthogonal chemistries to achieve this goal, which will allow us to recreate the tumor environment in vitro. Using this substrate, we will investigate aim 2: to test the hypothesis that stiffness inhomogeneities and local ligand type promote the dissemination of glioblastoma cells. Geometries designed to mimic blood vessels will be created such that their stiffness and ligand density and type are varied systematically to determine what conditions contribute to most efficient cell migration. Our last aim is to investigate the intracellular signaling pathways by which cells may interpret these cues. Aim 3 is to investigate the role of focal adhesion kinase in cell migration through peptide activated three-dimensional hyaluronic acid matrices with stiffness inhomogeneities. Importantly, FAK is often deregulated in many cancers and gliomas, suggesting it may play an important role in tumor dissemination. We expect this proposal to significantly contribute to the understanding of glioblastoma cell migration, specifically elucidating the factors that may promote dissemination from the host tumor. The results of this study will not only increase our understanding of the disease, but may also suggest possible therapeutic targets to inhibit cell migration.

描述（由申请人提供）：多形性胶质母细胞瘤（GBM）是人类中发现的最常见和最致命的脑癌形式。切除后肿瘤复发的中位时间仅为常规治疗后的6.9个月;诊断后的中位生存时间仅为1-2年。它不常见的侵略性迁移远离宿主肿瘤可能是无法完全手术切除肿瘤的原因，目前无法获得治愈性治疗。该项目的主要目标是更深入地了解GBM从宿主肿瘤中迁移的情况。人们普遍认为GBM的传播是沿着脑内沿着定义的“轨迹”发生的，包括血管系统和白色物质束，但对这种现象的了解很少。由这些轨道呈现的空间不均匀性-包括刚度和配体不均匀性-可能有助于引导细胞远离宿主肿瘤。在这个提议中，我们试图创建一个体外模型系统来复制肿瘤中存在的空间不均匀性，并询问空间刚度和配体不均匀性是否可以增强GBM细胞迁移。为实现这一目标，本提案有三个具体目标。目的1：建立一种正交控制基质刚度和配体连接的三维透明质酸平台。我们将使用正交化学的双光子激活来实现这一目标，这将使我们能够在体外重建肿瘤环境。使用这种基质，我们将研究目标2：检验硬度不均匀性和局部配体类型促进胶质母细胞瘤细胞传播的假设。设计用于模拟血管的几何形状将被创建，使得它们的刚度和配体密度和类型系统地变化，以确定什么条件有助于最有效的细胞迁移。我们的最后一个目标是研究细胞内的信号通路，细胞可以解释这些线索。目的3：研究黏着斑激酶在细胞通过具有刚度不均匀性的肽激活的三维透明质酸基质迁移中的作用。重要的是，FAK在许多癌症和神经胶质瘤中经常失调，这表明它可能在肿瘤扩散中发挥重要作用。我们希望这一建议将大大有助于了解胶质母细胞瘤细胞迁移，特别是阐明可能促进宿主肿瘤传播的因素。这项研究的结果不仅将增加我们对这种疾病的了解，而且还可能提出抑制细胞迁移的可能治疗靶点。