(PQ4) Mutations in the histone chaperone DAXX drive pancreatic neuroendocrine tumors not ductal adenocarcinomas
(PQ4) Mutations in the histone chaperone DAXX drive pancreatic neuroendocrine tumors not ductal adenocarcinomas
批准号:
9171873
负责人:
GUILLERMINA LOZANO
金额:
$20.88万
依托单位国家:
美国
项目类别:
财政年份:
2016
资助国家:
美国
项目状态:
已结题
起止时间:
2016-09-01 至 2018-08-31
关键词:
AddressAdenocarcinomaAllelesBiologicalBiological ModelsCRISPR screenCancer EtiologyCatalogingCatalogsCell LineCentromereChIP-seqCollectionDAXX geneDNADevelopmentDiseaseDuctalEmbryoEmployee StrikesEndocrineEpigenetic ProcessEtiologyEvaluationExhibitsExocrine pancreasFunctional disorderFutureGene ExpressionGenesGeneticGerm-Line MutationHistonesHumanImmunohistochemistryIncidenceIslet Cell TumorIslets of LangerhansKRAS2 geneKnockout MiceKnowledgeLesionLoss of HeterozygosityMalignant NeoplasmsMalignant neoplasm of pancreasMetastatic toModelingMolecularMolecular ChaperonesMusMutationNatural HistoryNegative StainingOncogenesOrganPancreasPancreatic Ductal AdenocarcinomaPathogenesisPathway interactionsPatientsPatternPhysiologicalPlayReagentRiskRoleTGFB1 geneTP53 geneTelomere MaintenanceTelomere PathwayTestingTimeTissuesTransplantationTumor Suppressor GenesTumor Suppressor ProteinsUnresectableVariantWorkcell typedefined contributionexome sequencinggain of function mutationgenome-wideimprovedin vivointerestloss of function mutationmouse modelmutantnovelresearch studytargeted treatmenttelomeretherapeutic targettumortumorigenesis
中文摘要
项目总结
英文摘要
Project Summary
While recent tumor sequencing efforts have provided a catalog of mutations that occur across many different
tumor types, the challenge now is to understand which mutations directly contribute to tumorigenesis. It has
also become clear that tissue and cellular context contribute a great deal to the ability of a mutation to cause
cancer, making it essential to study these effects in robust and relevant model systems. Despite arising from
the same organ, the two most frequent cancers of the pancreas are distinct, with different incidences and
natural histories, as well as unique mutation patterns. Pancreatic ductal adenocarcinomas (PDACs) have
nearly penetrant gain-of-function mutation in the KRAS oncogene, and loss-of-function mutations in the TP53
tumor suppressor gene. As these are amongst the most frequent mutations in human cancers, robust mouse
models have been built for this disease. Pancreatic neuroendocrine tumors (PanNETs), on the other hand,
have frequent loss of function mutations in the epigenetic regulators MEN1, DAXX and ATRX. These were the
first tumors identified to have mutations in DAXX and ATRX, and as such our understanding of how these
mutations contribute to cancer is limited. DAXX and ATRX interact and function as a chaperone for the histone
variant H3.3, specifically loading H3.3 into heterochromatic regions of DNA, including telomeres and
centromeres. This proposal aims to better understand the physiological consequences and molecular
mechanism downstream of DAXX loss that contribute to tumorigenesis and to address the provocative
question of why tumorigenesis in the endocrine pancreas is dramatically different than in the exocrine
pancreas. Using our recently developed conditional Daxx allele in the mouse, we will use genome-wide ChIP-
sequencing experiments for both Daxx and H3.3 to define the specific role of Daxx as an epigenetic regulator
in the pancreas. We will also use this new allele to build a relevant mouse tumor model of Daxx mutant
PanNETs. We will determine if Daxx loss alone, or in cooperation with Men1 loss (lesions that co-occur in a
subset of human tumors), can promote tumorigenesis. Additionally, we will conduct a CRISPR/Cas9 screen to
identify novel cooperating lesions and mechanisms in vivo. As PanNETs are rare, having a robust and faithful
model become even more valuable for understanding the pathogenesis of the disease and to identify novel
vulnerabilities and therapeutic targets. Combined, this work aims to uncover the potential cell-type specific
differences that impact tumorigenesis in the pancreas to advance our understanding of the molecular
mechanisms through which Daxx loss contributes to PanNETs and to develop novel models and reagents for
future studies.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Role of p53 Missense Mutations on Tumorigenesis in Vivo
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批准号:10097999
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项目类别:
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资助金额:$38.48万
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财政年份:2020
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依托单位:
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批准号:10549823
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依托单位:
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财政年份:2000
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负责人:GUILLERMINA LOZANO
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依托单位:
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项目类别:
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资助金额:$17.63万
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财政年份:2000
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依托单位:
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批准号:6198230
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项目类别:
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资助金额:$27.04万
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财政年份:1999
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依托单位:
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项目类别:
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资助金额:$17.63万
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财政年份:1999
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依托单位:
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财政年份:1999
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财政年份:1999
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财政年份:1999
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依托单位:
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批准号:7539214
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项目类别:
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资助金额:$25.6万
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财政年份:1999
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依托单位:
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依托单位:
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项目类别:
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资助金额:$34.2万
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财政年份:1999
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负责人:GUILLERMINA LOZANO
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依托单位:
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项目类别:
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资助金额:$37.53万
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财政年份:1999
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负责人:GUILLERMINA LOZANO
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依托单位:
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资助金额:$24.6万
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依托单位:
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资助金额:$26.1万
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财政年份:1999
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负责人:GUILLERMINA LOZANO
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资助金额:$25.6万
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负责人:GUILLERMINA LOZANO
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依托单位:
国内基金
海外基金
大肠癌发生机制的adenoma-adenocarcinoma pathway同serrated pathway的关系的研究
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批准号:30840003
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项目类别:专项基金项目
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资助金额:12.0万元
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批准年份:2008
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负责人:焦宇飞
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依托单位: