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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