Endothelial plasticity in glioma vascularization and therapy resistance

项目摘要 胶质母细胞瘤（GBM），IV级神经胶质瘤，是人类恶性肿瘤中最致命的一种，与其他恶性肿瘤不同， 血管发达GBM是最具侵袭性的原发性脑肿瘤，目前的中位生存期为 约14-16个月，主要是由于其对常规细胞毒性疗法的高抗性。丛生 血管系统表征了促进GBM进展并诱导血管生成的肿瘤微环境。 小生境介导的治疗抗性。然而，目前的抗血管治疗，主要针对亲- 包括VEGF在内的血管生成因子，尽管最初是开创性的，但已经遇到了重大困难， 治疗大多数恶性实体瘤（包括GBM）失败，可能是由于根除不足，或 肿瘤相关内皮细胞（EC）的功能抑制。我们最近的研究表明， 通过遗传重编程的可塑性是诱导EC对抗血管生成和血管生成的抗性的驱动力， 细胞毒性治疗。在这里，我们通过单细胞转录组分析肿瘤相关基因的初步研究， ECs揭示了ECs在基因工程中获得间充质和干细胞样基因标记， 小鼠GBM模型。利用人体标本和EC谱系追踪系统，我们的研究表明， GBM相关EC的治疗抗性。我们的体外和体内数据表明， 间充质干细胞（MSC）样细胞通过GBM中的Wnt激活诱导EC化学抗性。 因此，我们假设肿瘤EC中的间质和干细胞样基因重编程 在GBM中诱导治疗抗性。我们将通过追求以下目标来测试这一假设：1）定义 EC可塑性和处理抗性的分子机制，重点是Wnt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;和 将EC可塑性抑制与放疗/化疗或抗血管生成药物相结合的实验性治疗 在原位小鼠GBM模型中的治疗。成功完成拟议的工作将提供新的 深入了解肿瘤微环境依赖性治疗耐药性，并可能导致发展一种 新的治疗策略，靶向内皮可塑性的癌症。

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.