Tracing mechanisms of cellular heterogeneity and drug resistance in cancer
癌症细胞异质性和耐药性的追踪机制
基本信息
- 批准号:9050003
- 负责人:
- 金额:$ 3.43万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2016
- 资助国家:美国
- 起止时间:2016-03-01 至 2016-09-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAutomobile DrivingBacteriaBreast Cancer CellCRISPR interferenceCell LineageCellsChronic DiseaseClinicalClustered Regularly Interspaced Short Palindromic RepeatsCustomDNA SequenceData SetDrug DesignDrug ToleranceDrug resistanceDrug-sensitiveEpidermal Growth Factor Receptor Tyrosine Kinase InhibitorEpigenetic ProcessEquilibriumEvolutionGene ExpressionGene PoolGenealogyGenesGeneticGenetic HeterogeneityGoalsGrowthGuide RNAHeritabilityHeterogeneityHistonesHolidaysHypoxiaIndividualLabelLibrariesLifeMalignant NeoplasmsMolecularMutateNatural SelectionsNeoplasm MetastasisNon-Small-Cell Lung CarcinomaNude MiceNutrientParentsPatientsPharmaceutical PreparationsPhenotypePopulationProcessReadingRecording of previous eventsRecurrent diseaseResolutionSomatic MutationStimulusStochastic ProcessesSystemTechnologyTestingThe Cancer Genome AtlasTimeTreatment FailureTyrosine Kinase InhibitorUncertaintyVariantWritingXenograft procedurecancer cellcancer therapydaughter cellepigenetic drughistone modificationin vivoknock-downneoplastic cellnovelpressurepublic health relevancereconstructionresearch studyresistance genescreeningstemtheoriestooltumortumor heterogeneitytumorigenesis
项目摘要
DESCRIPTION (provided by applicant) A major challenge facing cancer treatment is tumor heterogeneity and selection of drug resistant clones. It is widely accepted that tumors possess large amounts of genetic heterogeneity due to branching subclonal evolution. Recently, it was discovered that heterogeneity also exists within isogenic tumor populations. Cellular heterogeneity has been attributed to stochastic processes intrinsic to gene expression and to epigenetic variability. Phenotypic switching has been observed in breast cancer cells that can reestablish equilibrium of subpopulations of stem, luminal, and basal phenotypes following perturbation. Moreover, many NSCLC patients show a reversible drug tolerance to Tyrosine Kinase Inhibitors. I hypothesize that distinct, semi- heritable epigenetic states underlie cellular
heterogeneity in tumors. I also predict this epigenetic plasticity exists due to incomplete resetting of histone modifications. Cellular heterogeneity has been a relatively unexplored phenomena due to a lack of technologies that can trace the fates of individual tumor cells. In this proposal I examine the mechanisms of cellular heterogeneity in tumors using a novel lineage tracking system, TRACER, where each cell writes its own unique barcode while recording the evolutionary history of ancestral cells. I propose to combine this transformative technology with pooled lentiviral CRISPR/gRNA libraries to provide a single cell resolution previously unavailable within pooled gene perturbation studies. Using these tools, I will quantitate the interconversion between semi-stable epigenetic states and define the heritability of these states while under selective pressures. The proposed experiments will illuminate the mechanisms of cellular heterogeneity and reversible drug tolerance in cancer cells and identify epigenetic drug resistance genes. The long term goal of TRACER studies is to identify the mechanisms that control the evolutionary trajectories of tumors and inform the design of drugs aimed at slowing or directing predictable paths of tumor evolution, with the ultimate goal of converting cancer from a lethal to a chronic disease.
项目成果
期刊论文数量(0)
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科研奖励数量(0)
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Gabriel Lee Eades其他文献
Gabriel Lee Eades的其他文献
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{{ truncateString('Gabriel Lee Eades', 18)}}的其他基金
MicroRNA-145 Regulation of Breast Cancer Stem CEll Self-Renewal
MicroRNA-145对乳腺癌干细胞自我更新的调节
- 批准号:
8842006 - 财政年份:2014
- 资助金额:
$ 3.43万 - 项目类别:
MicroRNA-145 Regulation of Breast Cancer Stem CEll Self-Renewal
MicroRNA-145对乳腺癌干细胞自我更新的调节
- 批准号:
8649641 - 财政年份:2014
- 资助金额:
$ 3.43万 - 项目类别:
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