Crosstalk between EGFR and TEAD Activity Directs Migration in Human Glioblastoma
EGFR 和 TEAD 活性之间的串扰指导人胶质母细胞瘤的迁移
基本信息
- 批准号:10079757
- 负责人:
- 金额:$ 1.1万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2019
- 资助国家:美国
- 起止时间:2019-01-15 至 2023-12-31
- 项目状态:已结题
- 来源:
- 关键词:ATAC-seqAdhesionsAffectAutomobile DrivingBehaviorBindingBiochemicalBiologyBrainBrain NeoplasmsCRISPR/Cas technologyCarcinomaCell Culture TechniquesCellsChIP-seqChromatinClustered Regularly Interspaced Short Palindromic RepeatsComplexDNADataDependenceDiffuseDisease ProgressionDown-RegulationElementsEngraftmentEpidermal Growth Factor ReceptorEpigenetic ProcessEquipmentExcisionExtracellular MatrixFDA approvedFamilyFeedbackFundingGene ExpressionGene TargetingGenesGenetic TranscriptionGenomicsGlioblastomaGliomaGoalsGrowthHistologyHumanHypoxiaImmunocompetentImmunofluorescence ImmunologicIn VitroInfiltrationInfiltrative GrowthKnock-inKnock-outLibrariesLinkMalignant NeoplasmsMeasuresMediatingMetabolicMetabolismMethodsModelingMolecularMorphologic artifactsMusNucleic Acid Regulatory SequencesOncogenicOperative Surgical ProceduresPDGFRA genePathway interactionsPatientsPenetrancePharmacologyPhenotypePreparationProto-Oncogene Proteins c-aktRNARecurrenceRoleSCID MiceSignal TransductionSliceSolid NeoplasmSystemTestingTimeToxic effectTreatment EfficacyTumor BurdenTumor Cell BiologyVerteporfinXenograft procedurebasecell growthcell motilitychemotherapycostexperimental studyfluorescence microscopegenome-widein vivoinhibitor/antagonistinsightmigrationneoplastic cellneuroinflammationnovelnovel therapeuticsoverexpressionpreventprogenitorprogramsqubitstem cell populationstressorsynergismtranscription factortranscriptome sequencingtumortumor growthtumor progression
项目摘要
SUMMARY
Glioblastoma (GBM) tumors manifest with a large, proliferative core and a diffusely infiltrative border, the latter
contributing to incomplete surgical resection and inevitable tumor recurrence. A better understanding of the
specific molecular pathways responsible for cell infiltration in GBM may thus provide novel and potentially more
effective opportunities for therapy. The biology of tumor cell infiltration/migration is complex and intimately
linked to its microenvironment, including adaptations for unique metabolic, hypoxic, motility, extracellular
matrix, and neuroinflammatory stressors. The pathways are difficult to recapitulate in glioma models that rely
on cell culturing. As cell fate decisions converge on the level of epigenetic control, one attractive strategy
to study the intricate biology of migration is to use epigenetics to define the transcriptional regulators of
migration in a system that closely resembles the native tumor cell state. In this proposal, we take advantage of
our lab's epigenetic expertise to study cell fate states in glioma stem cell populations (GSCs), directly
isolated from their tumor niche without pre-culture artifact [37-38,57]. Through the unique comparison of
open chromatin in freshly derived GSCs and normal germinal matrix progenitors, we were able to distinguish
the transcriptionally accessible regions in GSCs that specifically relate to cell migration (in final revisions). This
allowed us to infer the most salient transcription factor (TF) motifs within tumor-specific regulatory regions
linked to migration, where the TEAD family emerged as a top candidate. The TEAD TFs, along with their co-
activators YAP/TAZ, are the main effectors of the Hippo pathway, and have been studied for their oncogenic
regulatory role predominantly outside of the brain. To test the functional role of YAP-TEAD in GBM growth and
migration, we generated TEAD1 knockout in patient-derived GSCs using CRISPR/Cas9 and employed the
YAP-TEAD inhibitor, Verteporfin, to inhibit TEAD activity. Using both methods to inhibit TEAD1 activity, we
detected reduced capacity for cell migration in vitro and robust downregulation of EGFR and pERK expression.
EGFR knockout similarly displayed reduced migration in vitro, as well as decreased TEAD activity.
Based on this, here we hypothesize that TEAD activity regulates infiltrative growth in GBM, mediated at
least partially through an EGFR regulatory loop. To test this hypothesis, we aim to 1) systematically define
TEAD occupancy at open chromatin and downstream TEAD-target genes across GBM subtypes; 2a) dissect
mechanistically the relationship between Hippo-YAP/TAZ-TEAD and EGFR/RTK-ERK; 2b) define the role of
TEAD1 in regulating migration and growth in vitro and in/ex vivo, and its synergy with EGFR; and 3) test the
potential therapeutic efficacy of YAP-TEAD inhibitors, such as Verteporfin. We envision YAP/TAZ-TEAD as an
important regulator of infiltrative growth in GBM, where pharmacologic inhibition of its activity alleviates tumor
burden while also blocking oncogenic RTK effects, thus offering new therapeutic options for patients with GBM.
总结
项目成果
期刊论文数量(0)
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Nadejda Mincheva Tsankova其他文献
Nadejda Mincheva Tsankova的其他文献
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{{ truncateString('Nadejda Mincheva Tsankova', 18)}}的其他基金
Resolving SARS-Cov-2 tropism and COVID19 pathology in the brain
解决大脑中的 SARS-Cov-2 趋向性和 COVID19 病理学
- 批准号:
10170946 - 财政年份:2020
- 资助金额:
$ 1.1万 - 项目类别:
Crosstalk between EGFR and TEAD Activity Directs Migration in Human Glioblastoma
EGFR 和 TEAD 活性之间的串扰指导人胶质母细胞瘤的迁移
- 批准号:
10320954 - 财政年份:2019
- 资助金额:
$ 1.1万 - 项目类别:
Crosstalk between EGFR and TEAD Activity Directs Migration in Human Glioblastoma
EGFR 和 TEAD 活性之间的串扰指导人胶质母细胞瘤的迁移
- 批准号:
10543769 - 财政年份:2019
- 资助金额:
$ 1.1万 - 项目类别:
Defining the Chromatin Landscape and Transcriptional Drivers Of Proliferation and Migration In Human Glioblastoma.
定义人类胶质母细胞瘤的染色质景观和增殖和迁移的转录驱动因素。
- 批准号:
9572963 - 财政年份:2017
- 资助金额:
$ 1.1万 - 项目类别:
Defining the Chromatin Landscape and Transcriptional Drivers Of Proliferation and Migration In Human Glioblastoma.
定义人类胶质母细胞瘤的染色质景观和增殖和迁移的转录驱动因素。
- 批准号:
9436363 - 财政年份:2017
- 资助金额:
$ 1.1万 - 项目类别:
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