Modeling and druggable-genome screening of glioblastoma invasion using regional biopsy-guided biomaterials systems

使用区域活检引导的生物材料系统对胶质母细胞瘤侵袭进行建模和药物基因组筛选

• 批准号: 10237253
• 负责人: Manish Aghi
• 金额: $ 41.4万
• 依托单位: UNIVERSITY OF CALIFORNIA, SAN FRANCISCO
• 依托单位国家: 美国
• 财政年份: 2018
• 资助国家: 美国
• 起止时间: 2018-09-17 至 2023-08-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10237253
• 关键词: 3-Dimensional; Address; Automobile Driving; Biocompatible Materials; Biological Models; Biomedical Engineering; Biopsy; Blood capillaries; Brain Neoplasms; CD44 gene; CRISPR interference; Cells; Clustered Regularly Interspaced Short Palindromic Repeats; Collagen Type IV; Data; Diagnosis; Dimensions; Engineering; Excision; Exhibits; Extracellular Matrix Proteins; Failure; Fibronectins; Generations; Genome; Glioblastoma; Goals; Heterogeneity; Hyaluronic Acid; Hydrogels; In Vitro; Integrins; Knock-out; Laminin; Libraries; Ligands; Location; Magnetic Resonance Imaging; Malignant Neoplasms; Malignant neoplasm of brain; Mechanics; Mediating; Mediator of activation protein; Methods; Modality; Modeling; Nuclear; Patients; Process; Prognosis; Property; RNA Splicing; Recurrence; Role; Route; Sampling; Site; Structure; System; Technology; Thinking; Thinness; Tissue Engineering; Tumor Bank; Tumor Tissue; Tumor-associated macrophages; Variant; Work; base; cancer invasiveness; cell motility; combat; druggable target; effective therapy; falls; gray matter; high throughput screening; in vivo; loss of function; neoplastic cell; new therapeutic target; novel; patient derived xenograft model; screening; single cell technology; stressor; therapy development; three-dimensional modeling; tumor; tumor microenvironment; two-dimensional; white matter

PROJECT SUMMARY/ABSTRACT Glioblastoma (GBM) is a devastating brain tumor lacking effective treatments. This is largely due to invasion of GBM cells, which enables escape from resection and drives inevitable recurrence, typically 2 cm from the location at diagnosis. Progress in developing therapies to combat this process has been slow due to problems with the cells being studied and the methods of analysis. First, existing studies have failed to recognize that infiltrating GBM cells extending beyond the tumor edge have evolved a unique adaptive cellular machinery due to local stressors in their microenvironment. Unfortunately, these cells at the invasive tumor front are often not the ones sampled in studies analyzing banked tumor tissue, which is typically procured from the readily accessible central portions of the tumor. Another problem is that most studies of invasiveness have used two- dimensional (2D) culture systems coated with a thin layer of ECM proteins, which fail to capture the dimensionality, mechanics, and heterogeneity of GBM invasion. To address these limitations, our team has developed intriguing data using site-directed biopsies from GBM and has tissue engineered platforms to study invasion in vitro. Using site-directed biopsies, we have shown increased GBM cell invasiveness and increased expression of invasion-promoting integrins and extracellular matrix (ECM) splice variants outside versus inside enhancing MRI regions. We have also developed patient-derived xenografts (PDXs) from these site-directed biopsies that exhibit more invasiveness when arising from the tumor edge. Our team also became among the first to bioengineer 3D hydrogel systems as a discovery platform In GBM. We found that, as CD44-mediated peritumoral invasion falls, perivascular integrin-based motility increases. Here, we will build upon this intriguing data by investigating our central hypothesis that as GBM cells exit the tumor core, reciprocal interactions with the microenvironment drive a targetable transition from peritumoral to perivascular invasion. These goals will be accomplished through three aims: Aim 1 – Define changes in the tumor microenvironment promoting invasive change as tumor cells egress away from the central core to the outer edge of GBM; Aim 2 - Refine bioengineered culture models to replicate the microenvironment of the outer edge of GBM and identify the role of TAMs in driving invasion in this region; and Aim 3 - Define the role of integrins in the invasiveness of GBM cells from the outer tumor edge and identify druggable mediators of invasion in this region. To accomplish these goals, we will use novel PDXs and tissue engineered platforms, along with CRISPRi, single-cell technology, and site-directed biopsies. Our studies will discover novel mechanisms by which tumor cells and their microenvironment are altered to drive increased invasiveness as cells migrate away from the tumor core. This work will challenge conventional thinking by showing how GBM integrates distinct regional microenvironments. We will account for these distinctions when identifying novel druggable targets to disrupt GBM cell invasiveness, with potential applicability to other invasive cancers as well.

项目总结/文摘