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:
- 金额:$ 39.35万
- 依托单位:
- 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:
- 关键词:AcidosisApoptoticAutomobile DrivingBindingBiochemicalBrainBrain NeoplasmsCD36 geneCancer ControlCell DeathCell MaintenanceCellular StressCentral Nervous System NeoplasmsCuesDNA DamageDNA RepairDependenceDevelopmentDietary Fatty AcidDietary SupplementationDiseaseDouble EffectEctopic ExpressionEndogenous FactorsEndoplasmic ReticulumEnvironmentEnzymesFatty Acid DesaturasesFatty AcidsFrequenciesGenesGeneticGenetic TranscriptionGenomic InstabilityGlioblastomaGliomaGrowthHomeostasisHypoxiaImpairmentImplantIn VitroInositolLipid Synthesis PathwayLipidsMalignant - descriptorMalignant NeoplasmsMediatingModelingMolecularMusNF-kappa BNoseNutrientOncogenicParkinson DiseasePatientsPharmacologyPhase I Clinical TrialsPhenotypePopulationProliferatingPropertyProteinsRadiationRadiation therapyRecurrenceRegulationRegulatory ElementRoleRouteSTAT3 geneSaturated Fatty AcidsSignal PathwaySignal TransductionStearoyl-CoA DesaturaseSterolsStressSupplementationTestingTherapeuticTherapeutic EffectTranscriptional ActivationTreatment EfficacyUnsaturated Fatty AcidsWorkXenograft procedureanalogbasebeta cateninblood-brain barrier permeabilizationcancer stem cellclinical translationdesaturaseendoplasmic reticulum stressfatty acid metabolismin vivoinhibitor/antagonistlipid biosynthesismisfolded proteinmortalitymouse modelnew therapeutic targetnovelnovel therapeuticspreventresearch clinical testingresponseself-renewalsensorsmall hairpin RNAstem cell divisionstem cell modelstem cell proliferationstem cell self renewalstem cellsstem-like celltargeted treatmenttemozolomidetherapeutic targettherapy outcometherapy resistanttranscription factortreatment responsetumortumor behaviortumor growthtumor initiationtumor progressiontumorigenicuptake
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,
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。
项目成果
期刊论文数量(0)
专著数量(0)
科研奖励数量(0)
会议论文数量(0)
专利数量(0)
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Christian Elias Badr其他文献
Christian Elias Badr的其他文献
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{{ truncateString('Christian Elias Badr', 18)}}的其他基金
Translocon-regulated ER proteostasis in glioblastoma
胶质母细胞瘤中易位蛋白调节的内质网蛋白稳态
- 批准号:
10301296 - 财政年份:2021
- 资助金额:
$ 39.35万 - 项目类别:
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:
10665639 - 财政年份:2020
- 资助金额:
$ 39.35万 - 项目类别:
Screening for DNA damage response modulators in glioblastoma stem cells
胶质母细胞瘤干细胞中 DNA 损伤反应调节剂的筛选
- 批准号:
10038588 - 财政年份:2020
- 资助金额:
$ 39.35万 - 项目类别:
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:
10461146 - 财政年份:2020
- 资助金额:
$ 39.35万 - 项目类别:
Screening for DNA Damage Response Modulators in Glioblastoma Stem Cells
胶质母细胞瘤干细胞中 DNA 损伤反应调节剂的筛选
- 批准号:
10683338 - 财政年份:2020
- 资助金额:
$ 39.35万 - 项目类别:
Screening for DNA damage response modulators in glioblastoma stem cells
胶质母细胞瘤干细胞中 DNA 损伤反应调节剂的筛选
- 批准号:
10618739 - 财政年份:2020
- 资助金额:
$ 39.35万 - 项目类别:
Identifying vulnerabilities and therapeutic targets in Glioma Stem Cells
识别神经胶质瘤干细胞的脆弱性和治疗靶点
- 批准号:
8948656 - 财政年份:2015
- 资助金额:
$ 39.35万 - 项目类别:
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