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: 9887834
• 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/9887834
• 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.

项目概要/摘要： 乳腺浸润性导管癌（IDC）的预后较差。我们的项目主要关注代谢的作用 异常驱动侵袭性癌症以及炎症和氧化应激如何调节IDC 通过改变新陈代谢来增强攻击性IDC中的肿瘤细胞经常使用两种代谢途径之一： 糖酵解与葡萄糖催化剂到乳酸和线粒体氧化磷酸化（OXPHOS）。改变 基于肿瘤中不同细胞之间代谢物的释放和摄取的偶联代谢 微环境是IDC的一个特点。然而，目前尚不清楚代谢偶联是否会诱发癌症 侵略性靶向肿瘤代谢也可能是治疗IDC的有效方法， 开发新的预后和预测生物标志物。多个代谢区室通过 炎症、糖酵解和乳酸穿梭。成纤维细胞，这是最常见的非癌细胞， IDC肿瘤具有低OXPHOS、高糖酵解、高乳酸盐输出蛋白表达和高氧化还原性。 应力相反，癌细胞具有参与乳酸摄取的转运蛋白的高表达， 高OXPHOS和低糖酵解。我们已经鉴定了高TP 53诱导的糖酵解和凋亡调节剂， TIGAR在IDC癌细胞中作为肿瘤微环境代谢偶联的驱动因子。TIGAR降低 糖酵解通量作为果糖-2，6二磷酸酶。磷酸果糖激酶1（PFK 1）活性，这是一个 糖酵解中的限速步骤，由果糖2，6-二磷酸（Fru-2，6-P2）正向变构调节。 因此，TIGAR通过降低PFK 1活性降低糖酵解通量。我们的总体假设是肿瘤 TIGAR诱导的微环境代谢偶联足以诱导癌细胞凋亡， 增殖和抵抗细胞死亡，肿瘤微环境代谢解偶联将 克服肿瘤的侵袭性。我们的目标是将这些知识用于肿瘤微环境代谢 偶联以发现IDC攻击性的代谢机制。在目标1中，我们将检验以下假设： TIGAR诱导的代谢偶联足以促进侵袭性IDC。在目标2中，我们将测试 假设炎症信号是TIGAR诱导的代谢偶联的驱动因素， 侵略性最后，在目标3中，我们将检验氧化应激是TIGAR驱动因素的假设- 诱导代谢偶联和攻击性。总之，了解代谢相互作用 IDC肿瘤中不同细胞之间的侵袭性驱动可能为开发新的 治疗IDC。