Exposing the role of MYC in small cell carcinoma of the ovary hypercalcemic type
Exposing the role of MYC in small cell carcinoma of the ovary hypercalcemic type
批准号:
10728702
负责人:
April M. Weissmiller
金额:
$6.57万
依托单位国家:
美国
项目类别:
财政年份:
2023
资助国家:
美国
项目状态:
未结题
起止时间:
2023-07-05 至 2025-06-30
关键词:
ATP phosphohydrolaseAcuteAffectAgeAutomobile DrivingBindingBiologic CharacteristicBiological AssayCancer cell lineCell LineCell physiologyChromatinChromatin Remodeling FactorDataDiagnosisEssential GenesExposure toGene ActivationGene ExpressionGene Expression ProfileGenesGenetic TranscriptionGenomic approachGoalsHypercalcemiaImageImpairmentLeftLinkMaintenanceMalignant NeoplasmsMalignant neoplasm of ovaryModelingMolecularMutationOncogenesOncogenicOncoproteinsOperative Surgical ProceduresOvarianOvarian CarcinomaPathogenesisPatientsPhenotypePlayProcessProteinsPublishingRecurrenceRecurrent diseaseRegulationReportingResidual CancersResidual stateRoleSMARCA4 geneSMARCB1 geneSMARCC1 geneSWI/SNF Family ComplexShapesSmall Cell CarcinomaTestingTumor SuppressionTumor Suppressor ProteinsWomanWorkcancer cellcancer typecell typechemotherapyfallsgene networkgenetic approachgenome-wideinducible gene expressionloss of functionnovelnovel therapeutic interventionpredictive modelingprogramsprotein complextranscription factortranscriptometranscriptome sequencingtumortumorigenesistumorigenicyoung woman
中文摘要
项目总结/文摘
英文摘要
PROJECT SUMMARY/ABSTRACT
SCCOHT is rare and often fatal ovarian cancer, with the average age of diagnosis being around 24 years
old. The molecular pathogenesis of SCCOHT is overwhelmingly linked to mutations in the SMARCA4 gene,
which encodes the BRG1 subunit of the SWI/SNF chromatin remodeling complex. Numerous studies have
shown that loss of BRG1 impacts normal SWI/SNF function in several ways, which together most likely
conspire to drive the SCCOHT phenotype. SCCOHT cancers fall into a group of about 20% of all cancers
that have loss-of-function SWI/SNF subunit mutations. Across these cancers mechanisms are emerging
that can explain the maintenance of the cancer state following loss of particular SWI/SNF subunits. One
common finding is that in many SWI/SNF-altered cancers “residual” SWI/SNF complexes are retained that
function to promote a pro-tumorigenic gene expression program. A second and more new finding that is
emerging is that some underlying mechanisms of tumorigenesis may involve interactions between SWI/SNF
and oncoprotein transcription factors, such as MYC. Recently, activation of oncogenic MYC target gene
expression was reported in SCCOHT, a phenomenon that may be due to interactions between MYC and
SWI/SNF subunits. This project is built on the hypothesis that loss of critical SWI/SNF subunits can 1) allow
residual SWI/SNF complexes to alter gene expression patterns that overall promote cancer processes and
2) activate the functionality of MYC and may do so through changes in MYC-SWI/SNF interactions. Support
for this hypothesis comes from published data showing that in multiple SWI/SNF-altered cancer cell lines,
including SCCOHT, core residual SWI/SNF subunits are bound to chromatin at essential MYC target genes.
In addition, blocking residual SWI/SNF complex function in certain SWI/SNF-altered cancer cells decreases
expression of genes bound by MYC, suggesting that residual SWI/SNF complexes can facilitate MYC-target
gene expression. Together these data provide the rationale for examining the role of residual SWI/SNF
subunits and MYC in supporting oncogenic gene expression programs in SCCOHT, and point to the
possibility there there are broad, significant mechanisms at work across various SWI/SNF-altered cancers.
Specific Aim 1 will use genomic and genetic approaches to assess what residual SWI/SNF subunits are
doing in SCCOHT cells and how they influence pro-tumorigenic gene expression. Specific Aim 2 will define
the action of MYC in SCCOHT cells and expose the impact that both residual SWI/SNF subunits and BRG1
reintroduction has on MYC activities. At the completion of these studies we will know the gene networks
regulated by MYC and residual SWI/SNF subunits in SCCOHT cells and directly challenged the significance
of each in driving multiple facets of SCCOHT function.
期刊论文(0)
专著(0)
科研奖励(0)
会议论文
Determining the significance of the N-MYC-WDR5 interaction in neuroblastoma.
-
批准号:10290439
-
项目类别:
-
资助金额:$37.98万
-
财政年份:2021
-
负责人:April M. Weissmiller
-
依托单位:
海外基金