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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

基本信息

批准号：
8791309
负责人：
Andrew Rape
金额：
$ 2.36万
依托单位：
UNIVERSITY OF CALIFORNIA BERKELEY
依托单位国家：
美国
项目类别：
财政年份：
2013
资助国家：
美国
起止时间：
2013-02-01 至 2015-07-02
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/8791309
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 Geometry Glioblastoma Glioma Goals Health 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 scaffold stem cell biology therapeutic target tool tumor two-dimensional two-photon white matter

项目摘要

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）是人类最常见和致命的脑癌。常规治疗后肿瘤复发的中位时间仅为6.9个月；诊断后的中位生存时间仅为1-2年。它异乎寻常地向宿主肿瘤外的侵袭性迁移，可能是无法通过手术完全切除肿瘤的原因，使得目前无法治愈。该项目的总体目标是更深入地了解GBM远离宿主肿瘤的迁移。人们普遍认为，GBM沿着大脑中明确的“路径”传播，包括脉管系统和白质束，但对这一现象的了解甚少。这些轨迹所呈现的空间不均匀性——包括僵硬性和配体的不同源性——可能有助于引导细胞远离宿主肿瘤。在本提案中，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：建立基质刚度与配体附着正交控制的透明质酸三维平台。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。使用这种底物，我们将研究目的2：验证刚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。设计用来模拟血管的几何形状将被创造出来，这样它们的刚度、配体密度和类型就会系统地变化，以确定什么条件有助于最有效的细胞迁移。我们的最后一个目的是研究细胞内的信号通路，细胞可以解释这些线索。目的3是研究黏附激酶在细胞迁移中的作用，通过肽激活三维透明质酸基质的刚性不均匀。重要的是，FAK在许多癌症和胶质瘤中经常不受调节，这表明它可能在肿瘤传播中发挥重要作用。我们希望这一建议能够显著促进对胶质母细胞瘤细胞迁移的理解，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会增加我们对这种疾病的了解，而且可能会提出抑制细胞迁移的可能的治疗靶点。