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Targeting Lipid Metabolism in the Tumor Microenvironment

靶向肿瘤微环境中的脂质代谢

基本信息

批准号：
10471233
负责人：
Ashani T Weeraratna
金额：
$ 16.14万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2008
资助国家：
美国
起止时间：
2008-04-01 至 2024-08-31
项目状态：
已结题

来源：
https://reporter.nih.gov/project-details/10471233
关键词：
Affect Age Aging Antigen-Presenting Cells Automobile Driving BODIPY BRAF gene Binding Proteins Bone Marrow Carrier Proteins Cell Death Cells Collaborations Complex Data Dendritic Cells Esterification Exposure to FASN gene Fatty Acids Fibroblasts Generations Genetic Genetic Transcription Goals Growth Factor Human Immune Immune response Immunosuppression Immunotherapy In Vitro Insulin Invaded Knock-out Knockout Mice Ligase Link Lipid Peroxidation Lipids MAP Kinase Gene MEK inhibition MEKs Maintenance Mediating Melanoma Cell Metabolic Mitochondria Modeling Mus Myeloid-derived suppressor cells NADPH Oxidase PTEN gene Pathology Pathway interactions Patients Peroxidases Pharmaceutical Preparations Pharmacology Play Process Prognosis Proteomics Regulation Research Resistance Role Sampling Signal Transduction Site Stress Therapeutic Therapeutic Effect Triglycerides Tumor Immunity Very Long Chain Fatty Acid aged design erastin experimental study fatty acid elongases immune function in vivo inhibitor lipid metabolism lipidomics long chain fatty acid melanoma mouse model neoplastic cell neutrophil oxidized lipid peroxidation prevent programs response targeted treatment therapeutic target therapy development therapy resistant transcriptomics treatment response tumor tumor microenvironment tumor-immune system interactions uptake

项目摘要

Project Summary – Project 1 Our previous data have shown that the aged microenvironment drives resistance to targeted therapy, and may impact response to immunotherapy as well. Tumor cells undergo metabolic reprogramming in order to acquire resistance to BRAF/MEK inhibitors. We have found that one of the contributing factors to this resistance may be lipids. Aged or stressed fibroblasts secrete lipids, which are taken up by melanoma cells, promoting their ability to invade, and resist targeted therapy. These stromally-induced changes can also affect immune cells. Dendritic cells (DC) are required for the initiation and maintenance of immune responses and lipid accumulation in DC decreases their ability to act as antigen presenting cells. Myeloid derived suppressor cells (MDSCs) play a major role in regulation of antitumor immunity. These cells thrive on lipid metabolism and they accumulate and use oxidized lipids to augment their ability to suppress the immune microenvironment. We have implicated fatty acid (FA) transporter protein 2 (FATP2) in lipid accumulation by both tumor cells and PMN-MDSC, suggesting a complex crosstalk between multiple components of the TME. We propose to identify the mechanism and subsequent functional consequences of lipid accumulation in tumor cells and MDSCs. We will evaluate the effect of therapeutic targeting of lipid accumulation in MDSCs on the generation of immune responses in melanoma models, and on tumor cell fate and response to targeted therapy.

项目摘要-项目1 我们以前的数据表明，老化的微环境会导致对靶向治疗的抵抗，也可能影响免疫治疗的效果。肿瘤细胞经历代谢重编程，获得对BRAF/MEK抑制剂的抗性。我们发现其中一个因素阻力可能是脂质。衰老或应激的成纤维细胞分泌脂质，这些脂质被黑色素瘤细胞摄取，提高它们的入侵能力，抵抗靶向治疗。这些基质诱导的变化也可以影响免疫细胞。树突状细胞（DC）是启动和维持免疫系统所必需的。 DC中的脂质积累和免疫应答降低了它们作为抗原呈递细胞的能力。髓系衍生的抑制细胞（MDSC）在调节抗肿瘤免疫中起主要作用。这些细胞在脂质代谢，它们积累并使用氧化脂质来增强它们抑制免疫的能力，我们已经暗示脂肪酸（FA）转运蛋白2（FATP 2）在脂质积累，肿瘤细胞和PMN-MDSC两者，表明TME的多个组分之间的复杂串扰。我们建议确定脂质积累的机制和随后的功能后果，肿瘤细胞和MDSC。我们将评估MDSC中脂质积聚的治疗靶向作用，在黑色素瘤模型中免疫应答的产生，以及肿瘤细胞的命运和对靶向治疗