Targeting aberrant enhancer landscapes in pancreatic cancer
靶向胰腺癌中的异常增强子景观
基本信息
- 批准号:9816984
- 负责人:
- 金额:$ 41.31万
- 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:2019-07-02 至 2024-06-30
- 项目状态:已结题
- 来源:
- 关键词:AddressAdenocarcinoma CellBiological AssayCRISPR screenCellsCessation of lifeChromatinChromatin Remodeling FactorCollectionComplementComplexDependenceDevelopmentDiagnosisDiseaseDisseminated Malignant NeoplasmDuctal Epithelial CellElementsEmbryoEndodermEnhancersEpigenetic ProcessEventFutureGene Expression ProfileGenesGeneticGenetic Enhancer ElementGenetic TranscriptionGenomeGenomic approachGenomicsGoalsHTATIP geneHumanInterventionKnock-outLeadLocationMaintenanceMalignant neoplasm of pancreasMetastatic AdenocarcinomaModelingMolecularMutationNeoplasm MetastasisOrganoidsPancreatic Ductal AdenocarcinomaPatientsPatternPhenotypePolycombPrimitive foregut structureProcessRecurrenceResearchRoleSamplingSiteSourceSquamous CellSystemTestingTransplantationUp-Regulationbasecancer celleffective therapyepigenetic therapyexperimental studyfunctional genomicsin vivoinnovationinnovative technologiesinterestloss of functionneoplasticnoveloutcome forecastpancreatic cancer cellspancreatic cancer patientsprogenitorprogramstargeted treatmenttherapeutic targettraittranscription factortranscriptometumor progression
项目摘要
Project Summary/Abstract
The central goal of this project is to develop strategies to epigenetically reprogram pancreatic cancer cells to
diminish metastatic spread. This objective is based on our recent demonstration that pancreatic cancer
metastasis is accompanied by a stereotypical pattern of enhancer activation. We implicated the pioneer
transcription factor FOXA1 as a driver of enhancer reprogramming and of metastatic spread in this context. In
this proposal, we seek to define the enhancer-metastasis connection. In doing so, we seek to nominate a new
class of epigenetic targets, which might be uniquely capable of eliminating metastatic potential. In the first Aim
of this proposal, we will employ a functional genomics approach to perturb every FOXA1-regulated gene and
enhancer and determine whether FOXA1-dependent metastasis can be suppressed. This approach will take
advantage of our recent innovations in domain-focused CRISPR screening and will deepen our understanding
of the pro-metastatic components of this epigenetic program. In the second Aim of this proposal, we will
investigate the earliest steps of the enhancer reprogramming process that occur prior to FOXA1 upregulation.
This effort builds from our unexpected observation that metastasis-specific enhancers are already present in
an accessible chromatin state in pre-metastatic pancreatic tumor cells. This suggests that additional molecular
events occur prior to FOXA1 upregulation to set the stage for enhancer reprogramming during metastasis. We
will investigate the transcription factor FOXA2, which our experiments suggest is the critical bookmark that
opens up metastasis-specific enhancers in pre-metastatic cancer cells. In addition, we will determine how
repressive Polycomb complexes act to restrain enhancer activation prior to FOXA1 upregulation. By evaluating
the consequences of FOXA2/Polycomb perturbation, we will provide a proof-of-concept that metastasis-
associated enhancers can be effaced at early stages of pancreatic cancer progression. The final Aim of this
proposal will be to extend our enhancer mapping studies into the squamous-subtype of pancreatic cancer,
which is a recently defined disease entity associated with a particularly dismal prognosis. We will employ a
newly characterized complement of patient-derived pancreatic cancer organoids to compare enhancer profiles
of squamous-subtype versus the more classical form of this disease. We will identify master-regulators of this
squamous transcriptional program, and perform genetic experiments to determine the role of such factors in
promoting tumor progression and metastatic spread. We will also determine whether squamous cell identity in
PDA is associated with unique epigenetic dependencies. Collectively, the proposed research will provide a
mechanistic framework for developing epigenetic therapies that target the unique enhancer configuration of
metastatic pancreatic cancer cells.
项目总结/文摘
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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CHRISTOPHER VAKOC其他文献
CHRISTOPHER VAKOC的其他文献
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{{ truncateString('CHRISTOPHER VAKOC', 18)}}的其他基金
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