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。

• 批准号: 10687227
• 负责人: ERWIN G VAN MEIR
• 金额: $ 47.12万
• 依托单位: UNIVERSITY OF ALABAMA AT BIRMINGHAM
• 依托单位国家: 美国
• 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/10687227
• 关键词: Adhesions; Affect; Angiogenesis Inhibitors; 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; Invaded; Knowledge; Laboratories; Lead; Malignant Glioma; Malignant Neoplasms; Malignant neoplasm of brain; Mass Spectrum Analysis; Mediating; Membrane; Mesenchymal; Methylation; Micro Array Data; Molecular; Mus; N-terminal; Nature; Oncogenic; Operative Surgical Procedures; Orphan; Outcome; Pathway interactions; Patients; Peptides; Phenotype; Pilot Projects; Play; Prevention; Process; Property; Radiation therapy; Recurrent tumor; Regulation; Research; Role; Secure; Signal Pathway; Signal Transduction; Slice; Testing; Therapeutic; Thrombospondins; Transforming Growth Factor beta; Tumor Cell Invasion; Tumor Suppressor Proteins; Xenograft Model; Xenograft procedure; adhesion receptor; blood-brain barrier permeabilization; cancer cell; chemotherapy; 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

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 恶性胶质瘤具有高度侵袭性和致命性，迫切需要新的治疗方法 肿瘤的胶质母细胞瘤（GBM）患者在诊断后1-2年内死亡，尽管目前的常规治疗方法， 治疗，包括手术，放疗和化疗。肿瘤复发的一个主要驱动因素是浸润性肿瘤。 神经胶质瘤细胞的性质进入邻近的正常大脑，这是由间充质转录的激活驱动的。 程序.这种间充质转化通过细胞表面受体的细胞外刺激被激活， 生长因子如TGFβ1。本项目的总体目的是研究粘附的作用 G蛋白偶联受体B1（ADGRB 1/BAI 1）在间质转换和侵袭中的作用，并探索新的 GBM的相关机制为基础的治疗。ADGRB 1是一种特异性的孤儿粘附GPCR， 在大脑中表达。我们先前的研究表明，ADGRB 1的表达在患有糖尿病的患者中显著降低， GBM通过表观遗传沉默，这表明ADGRB 1丢失可能促进肿瘤形成。我们的新 初步数据显示，ADGRB 1低表达与胶质瘤的侵袭性和不良预后相关， 患者GBM细胞中ADGRB 1表达的恢复抑制了培养物中的间充质表型 和小鼠异种移植物。我们的初步研究进一步表明，ADGRB 1可以抑制TGFβ1驱动的间充质细胞增殖。 通过其第一个血小板反应蛋白1型重复序列（TSR 1）中的WxLWxLW基序进行过渡。这个主题 ADGRB 1与潜在的TGFβ1复合物结合并阻止TGFβ1成熟。基于这些结果，我们 假设ADGRB 1通过阻断TGFβ1介导的间充质干细胞， 用表观遗传学疗法转换和恢复其表达将代表一种新的治疗干预 对于GBM。为了验证我们的假设，我们提出了以下目标：（i）定义ADGRB 1如何负调节 间充质转化和胶质瘤侵袭，（ii）确定BAI 1如何拮抗TGFβ1前间充质 信号传导和（iii）评估BAI 1表达的表观遗传恢复是否可以抑制胶质瘤细胞侵袭。 体外和体内，并增加术后存活率。这些研究很重要，因为我们发现了一种特定的 BAI 1胞外区拮抗TGFβ1成熟和胶质瘤间质细胞分化 开关，提供了一种新的机制，拮抗这种致癌途径，可以利用 治疗上这些发现支持将这一新途径靶向于由以下因素驱动的癌症患者： 间质转化

项目成果

Mice lacking full length Adgrb1 (Bai1) exhibit social deficits, increased seizure susceptibility, and altered brain development.

• DOI: 10.1016/j.expneurol.2022.113994
• 发表时间: 2022-05
• 期刊: EXPERIMENTAL NEUROLOGY
• 影响因子: 5.3
• 作者: Shiu, Fu Hung;Wong, Jennifer C.;Yamamoto, Takahiro;Lala, Trisha;Purcell, Ryan H.;Owino, Sharon;Zhu, Dan;Van Meir, Erwin G.;Hall, Randy A.;Escayg, Andrew
• 通讯作者: Escayg, Andrew

Analysis of morphological characteristics of IDH-mutant/wildtype brain tumors using whole-lesion phenotype analysis.

• DOI: 10.1093/noajnl/vdab088
• 发表时间: 2021-01
• 期刊: Neuro-oncology advances
• 作者: Snyder JM;Huang RY;Bai H;Rao VR;Cornes S;Barnholtz-Sloan JS;Gutman D;Fasano R;Van Meir EG;Brat D;Eschbacher J;Quackenbush J;Wen PY;Lee JW
• 通讯作者: Lee JW