权益分类	功能权益	普通用户	{{item.name}}会员
{{category.name}}	{{benefitItem.name}}

Endothelial plasticity in glioma vascularization and therapy resistance

神经胶质瘤血管化和治疗抵抗中的内皮可塑性

基本信息

批准号：
10116668
负责人：
Yi Fan
金额：
$ 39.81万
依托单位：
UNIVERSITY OF PENNSYLVANIA
依托单位国家：
美国
项目类别：
财政年份：
2015
资助国家：
美国
起止时间：
2015-09-30 至 2025-11-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10116668
关键词：
Angiogenic Factor Area Blood Vessels C10 chemokine Cell Lineage Cell Proliferation Cell Therapy Cells Chemoresistance Chemotherapy and/or radiation Cytotoxic Chemotherapy Data Development Endothelial Cells Endothelium Failure Fibroblasts Functional disorder Genes Genetic Genetically Engineered Mouse Glioblastoma Glioma Goals Grant Human In Vitro Investigational Therapies KDR gene Kaposi Sarcoma Knockout Mice Lead Liver Fibrosis Malignant - descriptor Malignant Neoplasms Mediating Mesenchymal Mesenchymal Stem Cells Modeling Molecular Monitor Mus Myositis Nutrient Oxygen Pathologic Pharmacology Phenotype Phosphorylation Play Primary Brain Neoplasms Radio Refractory Resistance Role Science Signal Transduction Solid Neoplasm Specimen System Testing Therapeutic Therapeutic Effect Vascular Endothelial Growth Factors Vascularization Work angiogenesis base beta catenin bevacizumab cancer therapy cell motility chemotherapy coronary fibrosis cytotoxic driving force genetic signature in vivo insight kidney fibrosis knock-down melanoma mouse model novel novel therapeutic intervention novel therapeutics paracrine pre-clinical response single-cell RNA sequencing stem stem-like cell stemness temozolomide therapy resistant transcriptome transcriptome sequencing trend tumor tumor growth tumor microenvironment tumor progression tumorigenesis vascular abnormality

项目摘要

Project Summary Glioblastoma (GBM), the grade IV glioma, is among the most lethal of human malignancies, distinguished by prominent vascularity. GBM is the most aggressive primary brain tumor with a current median survival of about 14-16 months, largely due to its high resistance to conventional cytotoxic therapies. Overgrown vasculature characterizes the tumor microenvironment that fuels GBM progression and induces vascular niche-mediated therapeutic resistance. However, current anti-vascular therapy that primarily targets pro- angiogenic factors including VEGF, albeit initially groundbreaking, has encountered major difficulties and failures in treating most malignant solid tumors including GBM, likely due to insufficient eradication or functional inhibition of tumor-associated endothelial cells (ECs). Our recent studies suggest that EC plasticity by genetic reprogramming is a driving force that induces EC resistance to anti-angiogenic and cytotoxic treatments. Here, our preliminary study by single-cell transcriptome analysis of tumor-associated ECs reveals that ECs acquire mesenchymal and stemness-like gene signature in a genetically engineered mouse GBM model. Utilizing human specimens and EC lineage-tracing systems, our studies reveal robust treatment resistance in GBM-associated ECs. Our in vitro and in vivo data suggest that genetic reprogramming into mesenchymal stem cell (MSC)-like cells induces EC chemoresistance through Wnt activation in GBM. Therefore, we hypothesize that mesenchymal and stemness-like genetic reprogramming in tumor ECs induces therapy resistance in GBM. We will test this hypothesis by pursuing the following aims: 1) Define the molecular mechanism underlying EC plasticity and treatment resistance with a focus on Wnt activation; 2) Determine the in vivo role of c-Met/Wnt-mediated EC plasticity in tumor progression; and 3) Test experimental therapy that combines EC plasticity inhibition with radio/chemotherapy or anti-angiogenic therapy in orthotopic mouse GBM models. Successful completion of the proposed work will provide novel insights into tumor microenvironment-dependent treatment resistance, and may lead to development of a new therapeutic strategy by targeting endothelial plasticity in cancer.

项目摘要胶质母细胞瘤(GBM)是四级胶质瘤，是人类最致命的恶性肿瘤之一。通过突出的血管。基底节细胞瘤是最具侵袭性的原发脑瘤，目前中位生存期为大约14-16个月，主要是因为它对传统的细胞毒疗法具有很高的抵抗力。杂草丛生血管系统是肿瘤微环境的特征，它促进了基底膜的发展并诱导了血管的形成生态位介导的治疗耐药。然而，目前主要针对亲血管的抗血管治疗包括血管内皮生长因子在内的血管生成因子，尽管最初是开创性的，但遇到了重大困难和治疗包括基底膜在内的大多数恶性实体肿瘤失败，可能是由于根除或肿瘤相关内皮细胞(ECs)的功能抑制。我们最近的研究表明，欧共体基因重新编程的可塑性是导致EC对抗血管生成和抗肿瘤药物耐药的驱动力细胞毒性治疗。在此，我们通过单细胞转录组分析初步研究了肿瘤相关基因 ECS显示内皮细胞在基因工程中获得间充质和茎样基因特征小鼠肾小球基底膜模型。利用人类标本和EC血统追踪系统，我们的研究揭示了基底膜相关内皮细胞的耐药。我们的体外和体内数据表明，基因重新编程转化为间充质干细胞(MSC)样细胞，通过激活BM中的Wnt诱导EC产生化疗耐药。因此，我们假设肿瘤内皮细胞中的间充质和干细胞样基因重编程。在GBM中诱导治疗耐药。我们将通过追求以下目标来检验这一假设：1)定义 EC可塑性和治疗抗性的分子机制，重点是Wnt的激活； 2)确定c-Met/Wnt介导的EC可塑性在肿瘤进展中的体内作用；以及3)测试 EC可塑性抑制联合放化疗或抗血管生成的实验性治疗小鼠原位基底膜模型的治疗。拟议工作的成功完成将提供新的对肿瘤微环境依赖的治疗耐药性的洞察，并可能导致针对肿瘤内皮细胞可塑性的新治疗策略。