Differential role of different NAD+ kinase Isoforms in melanoma metastasis
不同 NAD 激酶亚型在黑色素瘤转移中的不同作用
基本信息
- 批准号:10436014
- 负责人:
- 金额:$ 38.77万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2022
- 资助国家:美国
- 起止时间:2022-05-01 至 2027-04-30
- 项目状态:未结题
- 来源:
- 关键词:AdoptedAffinity ChromatographyAnoikisAntioxidantsAutomobile DrivingBindingBlood CirculationCancer EtiologyCancer PatientCancer cell lineCarbonCell LineCellsCessation of lifeChIP-seqClustered Regularly Interspaced Short Palindromic RepeatsCytoplasmDataDependenceDiseaseDisease OutcomeEnvironmentEnzymesEventGeneticHomeostasisHumanImmunocompromised HostIn SituMalignant NeoplasmsMalignant neoplasm of pancreasMelanoma CellMetabolicMetabolic PathwayMetastatic toMitochondriaModelingMolecularMusMutationNAD+ kinaseNADPNatureNeoplasm Circulating CellsNeoplasm MetastasisNoduleNormal CellNormal tissue morphologyOrganOrganellesOxidation-ReductionOxidative StressPathway interactionsPatient-Focused OutcomesPatientsPhysiologicalPrimary NeoplasmProductionProtein IsoformsProtein Sequence AnalysisReactive Oxygen SpeciesReduced GlutathioneRegulationRegulatory ElementReporterResistanceRoleSignal TransductionStressTestingTherapeutic InterventionTranscription Initiation SiteTranscriptional RegulationUp-RegulationVisceralWorkcancer cellcancer survivalcell regenerationcell typeclinical predictorsclinically relevanteffective therapyexperiencein vitro Modelin vivomelanomametabolic profilemigrationmortalitymouse modelneoplastic cellnew therapeutic targetnoveloverexpressionpatient derived xenograft modelpromoterresponsesensorsubcutaneoustargeted treatmenttranscription factortumor
项目摘要
PROJECT SUMMARY
Metastasis is responsible for more than 90% of cancer patient mortality yet there are no therapies that specifically
target metastatic disease. Many of the current in vitro models of metastasis focus on the molecular mechanisms
of migration, invasion and/or surviving anoikis, but cannot recapitulate the complexity of the environment in which
metastasis occurs in vivo. Conversely, in mouse models of metastasis, it has been difficult to examine the
molecular mechanisms that enable cells to proceed through each distinct step of metastasis due to limited
material that can be isolated and infrequency of metastatic events in these models. For these reasons little is
known about the challenges facing metastasizing cells in vivo, and how they are overcome. We have previously
established a clinically relevant model of melanoma metastasis, using patient-derived xenografts (PDX) in
immunocompromised mice, that recapitulates the outcome of the disease of the patient in mice, to dissect the
metastatic cascade into distinct steps. Using this model, we have shown that metastasizing melanoma cells
undergo reversible metabolic adaptations to withstand oxidative stress in part through an increased dependence
on NADPH-generating enzymes in the one-carbon pathway. Our preliminary data also show an increase in
NADP+ levels in metastatic nodules compared to subcutaneous tumors, suggesting an increase in de novo
NADP+ synthesis. NADP+ is generated from NAD+ by NAD+ kinase (NADK). We observe higher levels of NADK
in metastatic nodules compared to subcutaneous tumors, where metastatic nodules express the isoform of
NADK with the highest activity, while subcutaneous tumors do not. We will test the hypothesis that metastasizing
melanoma cells upregulate a specific isoform of NADK to increase NADP+ production, increase oxidative stress
resistance and survival at different steps of the metastatic cascade.
Using both melanoma cell lines and PDX tumor cells, Aim 1 will determine the role of different NADK isoforms
in oxidative stress resistance, Aim 2 will define the mechanism of transcriptional regulation of NADK isoforms,
and Aim 3 will establish the role of different NADK isoforms as metastatic drivers in vivo. In addition, Aim 3 will
test how perturbation of oxidative stress in different organelles impacts metastasis. Together this work will
significantly contribute to our understanding of a novel mechanism of metabolic plasticity through upregulation
of a specific NADK isoform and identify organelle-specific metabolic pathways as novel therapeutically targetable
vulnerabilities in melanoma metastasis.
项目总结
项目成果
期刊论文数量(0)
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Elena Piskounova其他文献
Elena Piskounova的其他文献
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{{ truncateString('Elena Piskounova', 18)}}的其他基金
Differential role of different NAD+ kinase Isoforms in melanoma metastasis
不同 NAD 激酶亚型在黑色素瘤转移中的不同作用
- 批准号:
10613584 - 财政年份:2022
- 资助金额:
$ 38.77万 - 项目类别:
Identification and functional characterization of metabolic adaptations during melanoma metastasis
黑色素瘤转移过程中代谢适应的鉴定和功能表征
- 批准号:
9526121 - 财政年份:2016
- 资助金额:
$ 38.77万 - 项目类别:
Identification and functional characterization of metabolic adaptations during melanoma metastasis
黑色素瘤转移过程中代谢适应的鉴定和功能表征
- 批准号:
9109321 - 财政年份:2016
- 资助金额:
$ 38.77万 - 项目类别:
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