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

基本信息

批准号：
10530580
负责人：
Ubaldo Martinez Outschoorn
金额：
$ 34.97万
依托单位：
THOMAS JEFFERSON UNIVERSITY
依托单位国家：
美国
项目类别：
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/10530580
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 Disparate Down-Regulation Drug Targeting Enzymes Fibroblasts Fructose Future Genes Genetic Epistasis Glucose Glycolysis Glycolysis Induction 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 NF-kappa B Outcome Oxidation-Reduction Oxidative Phosphorylation Oxidative Stress Pathway interactions Pentosephosphate Pathway Phosphotransferases Prognostic Marker Proliferating Public Health Resistance Role Sampling Signal Transduction Stromal Cells TGFB1 gene TP53 gene Testing Therapeutic Transforming Growth Factor beta Tumor Promotion Variant cancer cell carcinogenesis 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

项目摘要

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.

项目摘要/摘要：乳房浸润性导管癌（IDC）的结局很差。我们的项目着重于代谢的作用异常驱动侵略性癌症以及炎症和氧化应激如何调节IDC 通过改变新陈代谢的侵略性。 IDC中的肿瘤细胞经常使用两种代谢途径之一：用葡萄糖分解代谢对乳酸和线粒体氧化磷酸化（OXPHOS）的糖酵解。改变代谢，基于肿瘤中不同细胞之间代谢物的释放和摄取耦合的代谢微环境是IDC的功能。但是，尚不清楚代谢耦合是否会诱导癌症侵略性。靶向肿瘤代谢也可能是治疗IDC的有效方法，并使我们能够开发新的预后和预测性生物标志物。多个代谢室通过炎症，糖酵解和乳酸的穿梭。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，乳酸出口剂的高表达和高氧化压力。相反，癌细胞的转运蛋白表达很高，参与乳酸的摄取，高氧气和低糖酵解。我们已经确定了高TP53诱导的糖酵解和凋亡调节剂（Tigar）在IDC癌细胞中是肿瘤微环境代谢偶联的驱动器。蒂加尔减少了糖酵解通量作为果糖-2,6双磷酸酶。磷酸 - 果糖 - 激酶1（PFK1）活性，这是一个糖酵解的速率限制步骤，受果糖2,6双磷酸（FRU-2,6-P2）的阳性变构调节。因此，蒂加尔通过降低的PFK1活性减少了糖酵解通量。我们的总体假设是肿瘤由Tigar诱导的微环境代谢耦合足以诱导癌细胞增殖和对细胞死亡的抵抗力以及肿瘤微环境的代谢解偶联将会克服肿瘤的侵略性。我们的目标是将这些知识用于肿瘤微环境代谢结合发现IDC侵略性的代谢机制。在AIM 1中，我们将检验以下假设 Tigar诱导的代谢耦合足以促进攻击性IDC。在AIM 2中，我们将测试假设炎症信号传导是Tigar诱导的代谢偶联和侵略性。最后，在AIM 3中，我们将检验以下假设：氧化应激是Tigar-的驱动力诱导代谢耦合和侵略性。总而言之，了解代谢相互作用如何 IDC肿瘤中不同细胞驱动侵略性可能会提供开发新颖的机会 IDC的治疗学。