Mechanisms underlying BAI1/ADGRB1 negative regulation of glioblastoma mesenchymal transition and invasion.

BAI1/ADGRB1 胶质母细胞瘤间质转化和侵袭负调控的机制。

基本信息

批准号：
10488569
负责人：
ERWIN G VAN MEIR
金额：
$ 44.29万
依托单位：
UNIVERSITY OF ALABAMA AT BIRMINGHAM
依托单位国家：
美国
项目类别：
财政年份：
2021
资助国家：
美国
起止时间：
2021-09-15 至 2026-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10488569
关键词：
Adhesions Affect BAI1 gene Binding Binding Proteins Binding Sites Brain Brain Neoplasms Cell Surface Receptors Cells Chemotherapy and/or radiation Clinical Complex Data Data Set Deuterium Development Diagnosis Ensure Epigenetic Process Excision Extracellular Domain Family G-Protein-Coupled Receptors Gene Expression Genes Genetic Transcription Glioblastoma Glioma Goals Growth Factor Growth Factor Receptors Health Human Hydrogen Image In Vitro Knowledge Laboratories Lead Malignant Glioma Malignant Neoplasms Malignant neoplasm of brain Mass Spectrum Analysis Mediating Mesenchymal Molecular Mus N-terminal Nature Oncogenic Operative Surgical Procedures Orphan Outcome Pathway interactions Patients Peptides Phenotype Pilot Projects Play Prevention Process Property Recurrence Regulation Research Role Secure Signal Pathway Signal Transduction Slice Testing Therapeutic Thrombospondins Time Transforming Growth Factor beta Tumor Cell Invasion Tumor Suppressor Proteins Xenograft Model Xenograft procedure adhesion receptor base blood-brain barrier permeabilization cancer cell chemoradiation conventional therapy crosslink epigenetic silencing epigenetic therapy experience extracellular in vitro Assay in vivo inhibitor innovation mRNA Expression medulloblastoma migration mouse model neoplastic cell novel novel therapeutic intervention novel therapeutics operation overexpression patient prognosis prevent programs restoration targeted treatment therapeutic target therapy resistant tumor tumor growth tumor progression

项目摘要

Project Summary New therapies are urgently needed for patients with malignant gliomas, which are highly invasive and lethal brain tumors. Patients with glioblastoma (GBM) die within 1-2 years of diagnosis despite current conventional therapies, including surgery, radiation and chemotherapy. A major driver of tumor recurrence is the infiltrative nature of the glioma cells into adjacent normal brain, which is driven by activation of a mesenchymal transcription program. This mesenchymal transition is activated through extracellular stimulation of cell surface receptors by growth factors such as TGFβ1. The overall purpose of the present project is to investigate the role of adhesion G protein-coupled receptor B1 (ADGRB1/BAI1) in the mesenchymal switch and invasion, and explore new therapies for GBM based on the related mechanisms. ADGRB1 is an orphan adhesion GPCR specifically expressed in the brain. We previously showed that ADGRB1 expression is significantly reduced in patients with GBM through epigenetic silencing, suggesting that ADGRB1 loss may facilitate tumor formation. Our new preliminary data show that low ADGRB1 expression correlates with invasion and poor outcome in glioma patients. Restoration of ADGRB1 expression in GBM cells suppresses the mesenchymal phenotype in culture and mice xenografts. Our pilot studies further suggest ADGRB1 can inhibit TGFβ1-driven mesenchymal transition through a WxLWxLW motif in its first thrombospondin type 1 repeat (TSR1). This motif mediates ADGRB1 binding to the latent TGFβ1 complex and prevents TGFβ1 maturation. Based on these results, we hypothesize that ADGRB1 acts as a brain tumor suppressor by blocking the TGFβ1-mediated mesenchymal switch and that restoration of its expression with epigenetic therapy will represent a novel therapeutic intervention for GBM. To test our hypothesis, we propose the following aims: (i) define how ADGRB1 negatively regulates the mesenchymal transition and glioma invasion, (ii), determine how BAI1 antagonizes TGFβ1 pro-mesenchymal signaling and (iii) evaluate whether epigenetic restoration of BAI1 expression can inhibit glioma cell invasion in vitro and in vivo, and augment survival post-operation. These studies are important as we identified a specific region in the extracellular domain of BAI1 that antagonizes TGFβ1 maturation and the glioma mesenchymal switch, providing a new mechanism for antagonizing this oncogenic pathway that can be exploited therapeutically. These findings support targeting this new pathway in patients whose cancers are driven by mesenchymal transition.

项目摘要对于恶性神经胶质瘤的患者，迫切需要新的疗法，这些疗法高度侵入性和致命性脑胶质母细胞瘤（GBM）的患者在诊断dospite电流常规的1 - 2年内死亡疗法，包括手术，放射和化学疗法。肿瘤复发的主要驱动力是浸润性神经胶质瘤细胞的性质进入相邻的正常脑，这是由间充质转录激活驱动的程序。通过细胞外刺激细胞表面受体通过生长因子，例如TGFβ1。本项目的总体目的是研究粘合剂的作用 G蛋白偶联受体B1（ADGRB1/BAI1）在间充质开关和入侵中，并探索新的基于相关机制的GBM疗法。 ADGRB1是专门的孤儿粘合剂GPCR 在大脑中表达。我们先前表明，患者的ADGRB1表达显着降低通过表观遗传沉默的GBM，表明ADGRB1损失可能促进肿瘤的形成。我们的新初步数据表明，低ADGRB1表达与胶质瘤的侵袭和不良结果相关患者。 GBM细胞中ADGRB1表达的恢复会抑制培养中的间充质表型和小鼠异种移植物。我们的试点研究进一步表明ADGRB1可以抑制TGFβ1驱动的间充质在其第一个血小板素类型1重复（TSR1）中通过WXLWXLW基序的过渡。这个主题介导 ADGRB1与潜在TGFβ1复合物结合并防止TGFβ1成熟。基于这些结果，我们假设ADGRB1通过阻断TGFβ1介导的间质抑制剂作为脑肿瘤抑制剂切换和通过表观遗传疗法的表达恢复将代表一种新型的热干预对于GBM。为了检验我们的假设，我们提出以下目的：（i）定义ADGRB1如何负面调节间充质转变和神经胶质瘤侵袭（II）确定BAI1如何拮抗TGFβ1pro-------- 信号传导和（iii）评估BAI1表达的表观遗传恢复是否可以抑制神经胶质瘤细胞的侵袭体外和体内，并增加生存后运作。这些研究很重要，因为我们确定了特定的 BAI1的细胞外域中的区域拮抗TGFβ1成熟和胶质瘤间质的区域开关，提供了一种可以探索这种致癌途径的新机制在治疗上。这些发现支持针对这种新途径的患者的癌症。间充质转变。