Tumor Microenvironment Metabolism in Invasive Ductal Carcinoma of the Breast

乳腺癌浸润性导管癌的肿瘤微环境代谢

• 批准号: 10300432
• 负责人: Ubaldo Martinez Outschoorn
• 金额: $ 35.69万
• 依托单位: THOMAS JEFFERSON UNIVERSITY
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-12-11 至 2024-11-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/10300432
• 关键词: Apoptosis; Apoptosis Regulation Gene; Automobile Driving; BCL2 gene; Binding; Biochemical; Carcinoma; Catabolism; Cell Compartmentation; Cell Death; Cell Proliferation; Cells; Clinical Trials; Coupled; Coupling; Cyclin D1; Data; Disease; Down-Regulation; Drug Targeting; Enzymes; Fibroblasts; Fructose; Future; Genes; Genetic Epistasis; Glucose; Glycolysis; Glycolysis Pathway; Growth; HIF1A gene; Human; IL6 gene; In Vitro; Inflammation; Inflammatory; Knowledge; Link; Malignant Epithelial Cell; Malignant Neoplasms; Mediating; Metabolic; Metabolic Pathway; Metabolism; Mitochondria; Modeling; Mus; Outcome; Oxidation-Reduction; Oxidative Phosphorylation; Oxidative Stress; Pathway interactions; Pentosephosphate Pathway; Phosphotransferases; Prognostic Marker; Public Health; Resistance; Role; Sampling; Signal Transduction; Stromal Cells; TGFB1 gene; TP53 gene; Testing; Therapeutic; Transforming Growth Factor beta; Variant; base; cancer cell; caveolin 1; ductal breast carcinoma; experimental study; in vivo; infiltrating duct carcinoma; knock-down; metabolic abnormality assessment; mitochondrial fitness; neoplastic cell; novel; novel therapeutics; outcome prediction; overexpression; patient subsets; predictive marker; sound; tumor; tumor growth; tumor metabolism; tumor microenvironment; uptake

Project Summary/Abstract: Outcomes in breast invasive ductal carcinoma (IDC) are poor. Our project focuses on the role of metabolic abnormalities driving aggressive cancer and how inflammation and oxidative stress regulate IDC aggressiveness via altered metabolism. Tumor cells in IDC frequently use one of two metabolic pathways: glycolysis with glucose catabolism to lactate and mitochondrial oxidative phosphorylation (OXPHOS). Altered metabolism with coupling based on release and uptake of metabolites between different cells in the tumor microenvironment is a feature of IDC. However, it is not known if metabolic coupling induces cancer aggressiveness. Targeting tumor metabolism may also be an effective way of treating IDC and allow us to develop new prognostic and predictive biomarkers. Multiple metabolic compartments are linked via inflammation, glycolysis and shuttles of lactate. Fibroblasts, which are the most common non-cancer cells in IDC tumors, have low OXPHOS, high glycolysis, high expression of lactate exporters, and high oxidative stress. Conversely, the carcinoma cells have high expression of transporters involved in the uptake of lactate, high OXPHOS and low glycolysis. We have identified high TP53 Induced Glycolysis and Apoptosis Regulator (TIGAR) in IDC carcinoma cells as a driver of tumor microenvironment metabolic coupling. TIGAR reduces glycolytic flux as a fructose-2,6 bisphosphatase enzyme. Phospho-fructo-kinase 1 (PFK1) activity, which is a rate limiting step in glycolysis, is positively allosterically regulated by fructose 2,6 bisphosphate (Fru-2,6-P2). Hence, TIGAR reduces glycolytic flux via reduced PFK1 activity. Our overall hypothesis is that tumor microenvironment metabolic coupling, induced by TIGAR, is sufficient to induce carcinoma cell proliferation and resistance to cell death and that tumor microenvironment metabolic uncoupling will overcome tumor aggressiveness. We aim to use this knowledge on tumor microenvironment metabolic coupling to discover metabolic mechanisms of IDC aggressiveness. In Aim 1, we will test the hypothesis that metabolic coupling induced by TIGAR is sufficient to promote aggressive IDC. In Aim 2 we will test the hypothesis that inflammatory signaling is a driver of TIGAR-induced metabolic coupling and aggressiveness. Finally in Aim 3 we will test the hypothesis that oxidative stress is a driver of TIGAR- induced metabolic coupling and aggressiveness. In summary, understanding how metabolic interactions between different cells in IDC tumors drive aggressiveness may provide opportunities to develop novel therapeutics for IDC.

项目总结/文摘: