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Role of ER stress and fatty acid metabolism in glioma stem cells

内质网应激和脂肪酸代谢在胶质瘤干细胞中的作用

基本信息

批准号：
10261413
负责人：
Christian Elias Badr
金额：
$ 39.35万
依托单位：
MASSACHUSETTS GENERAL HOSPITAL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-09-15 至 2025-07-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10261413
关键词：
Acidosis Apoptotic Automobile Driving Binding Biochemical Brain Brain Neoplasms CD36 gene Cancer Control Cell Death Cell Maintenance Cellular Stress Central Nervous System Neoplasms Cues DNA Damage DNA Repair Dependence Development Dietary Fatty Acid Dietary Supplementation Disease Double Effect Ectopic Expression Endogenous Factors Endoplasmic Reticulum Environment Enzymes Fatty Acid Desaturases Fatty Acids Frequencies Genes Genetic Genetic Transcription Genomic Instability Glioblastoma Glioma Growth Homeostasis Hypoxia Impairment Implant In Vitro Inositol Lipid Synthesis Pathway Lipids Malignant - descriptor Malignant Neoplasms Mediating Modeling Molecular Mus NF-kappa B Nose Nutrient Oncogenic Parkinson Disease Patients Pharmacology Phase I Clinical Trials Phenotype Population Proliferating Property Proteins Radiation Radiation therapy Recurrence Regulation Regulatory Element Role Route STAT3 gene Saturated Fatty Acids Signal Pathway Signal Transduction Stearoyl-CoA Desaturase Sterols Stress Supplementation Testing Therapeutic Therapeutic Effect Transcriptional Activation Treatment Efficacy Unsaturated Fatty Acids Work Xenograft procedure analog base beta catenin blood-brain barrier permeabilization cancer stem cell clinical translation desaturase endoplasmic reticulum stress fatty acid metabolism in vivo inhibitor/antagonist lipid biosynthesis misfolded protein mortality mouse model new therapeutic target novel novel therapeutics prevent research clinical testing response self-renewal sensor small hairpin RNA stem cell division stem cell model stem cell proliferation stem cell self renewal stem cells stem-like cell targeted treatment temozolomide therapeutic target therapy outcome therapy resistant transcription factor treatment response tumor tumor behavior tumor growth tumor initiation tumor progression tumorigenic uptake

项目摘要

Abstract Glioblastoma is the most malignant and common form of primary central nervous system tumors with high mortality and resistance to therapy. The presence of Glioma stem cells (GSCs) within the tumor, further complicates treatment, owing to the role of GSCs in promoting therapeutic resistance and tumor recurrence. Identifying Intrinsic and extrinsic factors that contribute to GSCs maintenance thus influencing tumor growth, could offer new therapeutic opportunities to treat this fatal disease. We recently showed that the desaturation of fatty acids (FA) is essential for maintaining GSCs self-renewal, proliferation, and in vivo tumor initiation properties. Pharmacological targeting of the desaturase enzyme Stearoyl CoA Desaturase 1 (SCD1) is particularly toxic due to the accumulation of saturated FA, which promotes apoptotic cell death, and achieves a remarkable therapeutic outcome in xenograft mouse models. Our results demonstrate that the dependence of GSCs on FA desaturation presents an exploitable vulnerability to target glioblastoma. However, regulation mechanisms driving key lipogenic enzymes such as SCD1, as well as the molecular role of FA in GSCs maintenance and plasticity remains unclear. Based on our preliminary results, we propose that stress signaling through the endoplasmic reticulum (ER stress), promotes the transcriptional activation of SCD1 as well as oncogenic signaling pathways downstream of SCD1 that are essential for GSCs maintenance. The objective of this proposal is to: 1) Define the role of ER stress in activating lipogenesis and oncogenic signaling that promote GSC self-renewal and increase tumorigenic potential. 2) Exploit the dependency of GSCs on adaptive ER stress signaling to test targeted therapeutics in patient-derived orthotopic GSCs mouse models. Upon completion, this work will elucidate novel mechanisms of plasticity and survival in GBM cancer stem cells and identify novel targeted therapeutics for clinical evaluation in GBM patients.

摘要胶质母细胞瘤是原发性中枢神经系统肿瘤中最恶性和最常见的形式，具有较高的死亡率和治疗抵抗力。肿瘤内胶质瘤干细胞(GSCs)的存在，进一步由于GSCs在促进治疗耐药和肿瘤复发方面的作用，使治疗复杂化。确定有助于GSCs维持从而影响肿瘤生长的内在和外在因素，可以为治疗这种致命疾病提供新的治疗机会。我们最近发现，脂肪酸(FA)的去饱和对于维持GSCs的自我更新是必不可少的，增殖和体内肿瘤启动特性。去饱和酶硬脂酰基的药理靶向性 CoA去饱和酶1(SCD1)的毒性尤其大，因为饱和脂肪酸的积累促进了细胞的凋亡细胞死亡，在异种移植小鼠模型上取得了显著的治疗效果。我们的结果表明 GSCs对FA去饱和度的依赖是靶向胶质母细胞瘤的易受攻击性。然而，驱动关键的造脂酶的调节机制，如SCD1，以及 FA在GSCs维持和可塑性中的作用尚不清楚。根据我们的初步结果，我们建议通过内质网的胁迫信号(内质网应激)，促进SCD1的转录激活以及SCD1下游的致癌信号通路，这些信号通路对GSCs的维持至关重要。这个这项建议的目的是：1)确定内质网应激在激活脂肪生成和致癌信号中的作用促进GSC自我更新，增加致瘤潜能。2)利用GSC对适应性内质网应激信号在患者来源的原位GSCs小鼠模型中测试靶向治疗。这项工作完成后，将阐明GBM癌症干细胞的可塑性和存活的新机制。并确定新的靶向治疗方法，用于GBM患者的临床评估。