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.
Triple-negative breast cancer (TNBC) is a highly aggressive clinical breast cancer subtype with few treatment options, but recent studies discovered TNBC is addicted to one of the amino acids, glutamine. In this project, we will study how tumor blood vessel utilizes glutamine to promote tumor growth and metastasis. The success of this project will provide insight into glutamine metabolism within the tumor blood vessel as a potential molecular vulnerability that could be exploited therapeutically to improve outcomes for patients with TNBC, and possibly other cancers.
