The Role of Vascular Endothelial Glutaminase in Tumor Vessel Normalization and Response to Therapy

项目总结/摘要 肿瘤血管提供营养和氧气，并消除肿瘤组织的废物。 然而，肿瘤相关血管功能失调且结构异常。他们是 通常渗漏和弯曲，血流混乱，导致药物输送减少， 减少免疫细胞的浸润。完全阻断肿瘤血管形成， 导致缺氧、营养应激和增加的肿瘤细胞运动性和转移。一个新 修复异常肿瘤血管系统的概念，称为肿瘤血管正常化， 研究了改善肿瘤血管灌注和氧合，减少转移， 提高癌症免疫治疗功效。几种机制，包括抑制 内皮中的有氧糖酵解已显示改善肿瘤血管正常化。 除了糖酵解，谷氨酰胺代谢是EC增殖和迁移所必需的。 虽然谷氨酰胺代谢在癌症背景下得到了很好的研究，但其在肿瘤血管生成中的作用仍然是一个未知的问题。 内皮细胞（TEC）的研究知之甚少。使用内皮特异性谷氨酰胺酶敲除 小鼠模型和TNBC/基底细胞样细胞系，我建议通过研究 血管内皮转氨酶在肿瘤血管正常化、肿瘤生长、转移和 对治疗的反应。为了实现这个目标，我将首先评估肿瘤血管的周细胞， 迂曲度、直径、灌注和渗漏，以及肿瘤浸润淋巴细胞， 内皮细胞GLS缺失（目的1）。此外，我将使用小鼠肿瘤模型， 在TEC中GLS敲除的背景下，评估肿瘤生长、转移和对两者的反应 化疗和免疫治疗（目的2）。该项目的成功将提供翻译 在治疗侵袭性乳腺癌TNBC或其他癌症的影响，并会给我 知识和经验的科学方法，以启动我的职业生涯作为一个独立的 调查员

Project Summary/Abstract Tumor blood vessels provide nutrition and oxygen and eliminate waste from tumor tissue. However, tumor-associated vessels are dysfunctional and structurally abnormal. They are often leaky and tortuous with chaotic blood flow, resulting in decreased drug delivery and reduced infiltration of immune cells. Complete blockade of tumor blood vessel formation has resulted in hypoxia, nutrient stress, and increased tumor cell motility and metastasis. A new concept to repair abnormal tumor vasculature, known as tumor vessel normalization, has been investigated to improve tumor vessel perfusion and oxygenation, reduce metastasis and increase efficacy of cancer immunotherapy. Several mechanisms, including inhibition of aerobic glycolysis in endothelium, have been shown to improve tumor vessel normalization. In addition to glycolysis, glutamine metabolism is required for proliferation and migration of ECs. Although glutamine metabolism is well studied in the context of cancer, its role in tumor vascular endothelial cells (TEC) is poorly understood. Using endothelium-specific glutaminase knockout mouse model and TNBC/basal-like cell lines, I propose to fill this gap by investigating the role of vascular endothelial glutaminase in tumor vessel normalization, tumor growth, metastasis, and response to therapy. To achieve this goal, I will first assess tumor vasculature for pericytes, tortuosity, diameter, perfusion, and leakiness, as well as tumor infiltrating lymphocytes, following GLS deletion from endothelial cells (Aim 1). Furthermore, I will use murine tumor models in the context of GLS knockout in TEC and assess tumor growth, metastasis, and response to both chemotherapy and immunotherapy (Aim 2). The success of this project will provide translational impact in the treatment of aggressive breast cancer TNBC or other cancers and will give me the knowledge and experience in the scientific method to launch my career as an independent investigator.