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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：
9791684
负责人：
Ashani T Weeraratna
金额：
$ 15.82万
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/9791684
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 Immunosuppressive Agents 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 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/antagonist lipid metabolism long chain fatty acid melanoma mouse model neoplastic cell neutrophil outcome forecast oxidized lipid peroxidation prevent programs response targeted treatment therapeutic target therapy development therapy resistant transcriptomics tumor tumor microenvironment 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》 -- 我们之前的研究数据显示，老龄化的微环境驱使人们对靶向治疗、治疗和治疗产生抵抗力。可能也会影响对免疫治疗的反应。肿瘤细胞可能会经历新的代谢和重新编程过程，以便更好地应对。获得对BRAF/MEK药物抑制剂的抵抗力。我们还发现，导致这种情况的主要因素之一。抵抗可能是脂质。随着年龄的增长或压力的增加，成纤维细胞会分泌脂类，而这些脂类则被黑色素瘤细胞所吸收。提高他们的能力，包括入侵、攻击和抵抗有针对性的治疗。这些疾病是由闪电诱导的，他们也可以改变。影响免疫调节细胞。树突状细胞(DC)是调节免疫调节系统启动和维持的必需细胞。树突状细胞的反应和脂质的堆积降低了他们作为抗原呈递干细胞的能力。衍生的肿瘤抑制因子细胞(MDSCs)在其抗肿瘤免疫的调节过程中发挥着重要的作用，使这些干细胞依靠干细胞而茁壮成长。脂类代谢紊乱，他们会积累脂肪，并利用氧化的脂类来增强他们抑制免疫功能的能力。微环境。我们已经发现，脂肪酸(FA)和转运蛋白2(FATP2)与人体内脂肪堆积有关。这两种细胞都是肿瘤细胞，也都是PMN-nMDSC，这表明TME的多个主要组件之间存在复杂的串扰。我们将提出一些建议，以进一步确定血脂积累的作用机制，以及随后的功能和后果。肿瘤细胞和骨髓间充质干细胞。我们将继续评估靶向治疗药物的疗效，以减少骨髓间充质干细胞中脂质的积累。在建立黑色素瘤模型的基础上，研究了第二代免疫应答对肿瘤细胞命运的影响以及对免疫应答的影响。有针对性的治疗。