Leveraging Gα12 signaling to treat glioblastoma
利用 Gα12 信号传导治疗胶质母细胞瘤
基本信息
- 批准号:10649241
- 负责人:
- 金额:$ 7.9万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2023
- 资助国家:美国
- 起止时间:2023-04-01 至 2024-03-17
- 项目状态:已结题
- 来源:
- 关键词:AttenuatedBehaviorBrainCell AdhesionCell Culture TechniquesCell Death InductionCell LineCell SurvivalCellsCoupledCouplingDisease remissionDoseEngraftmentExposure toG Protein-Coupled Receptor SignalingG-Protein-Coupled ReceptorsGNA12 geneGTP-Binding Protein alpha Subunits, GsGTP-Binding ProteinsGene ExpressionGene TargetingGenesGeneticGenetic TranscriptionGlioblastomaGliomaGoalsHeterotrimeric G Protein SubunitHumanImplantIn VitroInvadedLabelLuciferasesMalignant neoplasm of brainMediatingMesenchymalMusNeurosphereOperative Surgical ProceduresPatientsPredispositionPrimary Brain NeoplasmsPrognosisRadiationRadiation ToleranceRadiation therapyRadiosensitizationReceptor SignalingRecurrenceRecurrent diseaseReporterResearchResistanceRiskRoleSignal PathwaySignal TransductionTestingThe Cancer Genome AtlasTherapeutic InterventionTumor Stem CellsUp-RegulationXenograft procedurebrain tissuecell growthcell motilitydesigner receptors exclusively activated by designer drugsgain of functiongenetic approachimage guidedimprovedin silicoin vivoinnovationirradiationknock-downneoplastic celloverexpressionprecision medicineprogramsradiation responsereceptorresponseself-renewalsmall hairpin RNAstandard of carestem cell genesstem cellsstemnesstranscriptome sequencingtumortumor growth
项目摘要
Abstract
Glioblastoma multiforme, one of the most aggressive primary brain tumors, has a dismal
prognosis despite treatment advancements in the past decades. Low patient survival is driven by
disease recurrency after a period of remission. GBM is a highly invasive tumor, which makes
surgical recession difficult. G-protein coupled receptors are increasingly recognized for their ability
to regulate tumor growth. Many of these receptors signal through their coupling to the alpha
subunit of the heterotrimeric G-protein Ga12. In silico interrogation of GBM in The Cancer
Genome Atlas reveals marked upregulation of GNA12, the gene encoding G⍺12, concomitant
with overexpression of G-protein coupled receptors (GPCRs) that signal through this G-protein.
We recently determined that targeting G⍺12 in human glioma stem cells (GSCs) attenuates tumor
cell self-renewal, expression of stem cell genes, and invasion. Concordantly G⍺12 knockdown
(KD) reduced invasion of tumors from orthotopically engrafted GSC cells in vivo. Reciprocally,
chemogenetic activation of G⍺12 increased invasion. G⍺12 KD tumors assessed by RNA seq
showed reduced expression of cell adhesion and migration genes, as well as increased
expression of proneural genes. The observed changes in migratory behavior and gene expression
suggest that G⍺12 signaling promotes a proneural-to-mesenchymal transition. The evidence that
G⍺12 signaling regulates transcriptional programs for stemness and invasion of GSCs identifies
this as a potential signaling node for therapeutic intervention. Surgery followed by radiation
therapy is the standard of care for GBM. Decreases in stemness and invasiveness, associated
with a more proneural state, would be predictive of improved sensitivity to radiation therapy which
could in turn ameliorate disease recurrence and damage to healthy brain tissue. Our short-term
goal is to provide evidence for enhanced GSC susceptibility to radiation treatment in cells lacking
G⍺12 signaling. We will use single dose irradiation of GSCs in cell culture and in tumor bearing
mice using image-guided irradiation. Our innovative approach leverages the newly discovered
role of G⍺12 on tumor growth and invasiveness to improve GBM treatment. The ability to evaluate
radiosensitization, elicited by blockade of G⍺12 signals, in human patient derived glioma cells,
using image-guided irradiation is consistent with precision medicine approaches. Thus, our
findings could impact radiation treatment of resistant tumors and improve GBM patient survival.
If successful, our studies will be the first to demonstrate the benefit of targeting G⍺12 signaling in
association with radiation to treat GBM and will implicate G⍺12-coupled receptors and their
transcriptionally regulated gene targets as potential points of therapeutic intervention.
摘要
项目成果
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