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

• 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
• 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

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， 死亡率和对治疗的抵抗力。胶质瘤干细胞（GSC）在肿瘤内的存在， 由于GSC在促进治疗抗性和肿瘤复发中的作用，使治疗复杂化。 确定有助于GSC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GSC自我更新至关重要， 增殖和体内肿瘤引发特性。去饱和酶硬脂酰的药理学靶向 CoA去饱和酶1（SCD 1）由于饱和FA的积累而具有特别的毒性，其促进细胞凋亡 细胞死亡，并在异种移植小鼠模型中获得显著的治疗效果。我们的研究结果表明 GSC对FA去饱和的依赖性呈现出靶向胶质母细胞瘤的可利用的脆弱性。 然而，驱动关键脂肪生成酶如SCD 1的调节机制，以及 FA在GSC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， 通过内质网的应激信号（ER应激）促进SCD 1的转录激活 以及SCD 1下游的致癌信号通路，其对于GSC维持是必需的。的 本研究的目的是：1）明确ER应激在激活脂肪生成和致癌信号传导中的作用 促进GSC自我更新并增加致瘤潜力。2)利用全球供应链对 适应性ER应激信号传导，以在患者来源的原位GSC小鼠模型中测试靶向治疗剂。 完成后，这项工作将阐明GBM癌症干细胞可塑性和存活的新机制 并鉴定用于GBM患者临床评价的新型靶向治疗剂。