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:10613584
- 负责人:
- 金额:$ 38万
- 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 DrivingBindingCancer EtiologyCancer PatientCancer cell lineCarbonCell LineCellsCessation of lifeChIP-seqCirculationClustered Regularly Interspaced Short Palindromic RepeatsCytoplasmDataDependenceDiseaseDisease OutcomeEnvironmentEnzymesEventFrequenciesGeneticHomeostasisHumanImmunocompromised HostIn SituInvadedMalignant NeoplasmsMalignant neoplasm of pancreasMelanoma CellMetabolicMetabolic PathwayMitochondriaModelingMolecularMusMutationNAD+ kinaseNADPNatureNeoplasm Circulating CellsNeoplasm MetastasisNoduleNormal CellNormal tissue morphologyOrganOrganellesOxidation-ReductionOxidative StressPathway interactionsPatientsPhysiologicalPrimary NeoplasmProductionProliferatingProtein IsoformsProtein Sequence AnalysisReactive Oxygen SpeciesReduced GlutathioneRegulationRegulatory ElementReporterResistanceRoleSignal TransductionStressTestingTherapeutic InterventionTherapeutically TargetableTranscription Initiation SiteTranscriptional RegulationUp-RegulationVisceralWorkcancer cellcancer survivalcell regenerationcell typeclinical predictorsclinically relevanteffective therapyexperiencein vitro Modelin vivomelanomametabolic profilemigrationmortalitymouse modelneoplastic cellnew therapeutic targetnovelnovel therapeuticsoverexpressionpatient derived xenograft modelpromoterresponsesensorsubcutaneoustargeted treatmenttranscription factortumortumor progression
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.
项目摘要
转移是导致超过90%的癌症患者死亡的原因,但没有特异性的治疗方法,
靶向转移性疾病。目前许多体外转移模型都集中在转移的分子机制上
迁移,入侵和/或生存的失巢凋亡,但不能概括的复杂环境中,
转移发生在体内。相反,在转移的小鼠模型中,很难检查肿瘤的转移。
分子机制,使细胞能够通过每个不同的步骤转移,由于有限的
材料可以被隔离,并且在这些模型中很少发生转移事件。由于这些原因,
了解体内转移细胞面临的挑战,以及如何克服这些挑战。我们先前已经
建立了一个临床相关的黑色素瘤转移模型,使用患者来源的异种移植物(PDX),
免疫受损小鼠,其在小鼠中概括患者疾病的结果,以解剖
转移级联成不同的步骤。利用这个模型,我们已经证明转移性黑色素瘤细胞
经历可逆的代谢适应,部分通过增加依赖性来抵抗氧化应激,
对一碳途径中的NADPH生成酶的影响。我们的初步数据还显示,
与皮下肿瘤相比,转移性结节中的NADP+水平,表明新发肿瘤增加。
NADP+合成。NADP+由NAD+通过NAD+激酶(NADK)产生。我们观察到较高水平的NADK
与皮下肿瘤相比,转移性结节表达
NADK具有最高活性,而皮下肿瘤没有。我们将检验转移性肿瘤
黑色素瘤细胞上调NADK的特异性亚型以增加NADP+的产生,增加氧化应激,
在转移级联的不同阶段的抵抗和存活。
使用黑色素瘤细胞系和PDX肿瘤细胞,Aim 1将确定不同的NADK亚型的作用,
在氧化应激抗性中,Aim 2将定义NADK同种型的转录调节机制,
目的3将确定不同NADK同种型作为体内转移驱动因子的作用。此外,Aim 3将
测试不同细胞器中氧化应激的扰动如何影响转移。这项工作将
对我们理解一种新的代谢可塑性机制有重要贡献,
特异性NADK同种型,并将细胞器特异性代谢途径鉴定为新的治疗靶点
黑色素瘤转移的脆弱性。
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)
数据更新时间:{{ journalArticles.updateTime }}
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
数据更新时间:{{ journalArticles.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ monograph.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ sciAawards.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ conferencePapers.updateTime }}
{{ item.title }}
- 作者:
{{ item.author }}
数据更新时间:{{ patent.updateTime }}
Elena Piskounova其他文献
Elena Piskounova的其他文献
{{
item.title }}
{{ item.translation_title }}
- DOI:
{{ item.doi }} - 发表时间:
{{ item.publish_year }} - 期刊:
- 影响因子:{{ item.factor }}
- 作者:
{{ item.authors }} - 通讯作者:
{{ item.author }}
{{ 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:
10436014 - 财政年份:2022
- 资助金额:
$ 38万 - 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:
$ 38万 - 项目类别:
相似海外基金
Cellular membrane affinity chromatography kit for drug discovery
用于药物发现的细胞膜亲和层析试剂盒
- 批准号:
10506915 - 财政年份:2021
- 资助金额:
$ 38万 - 项目类别:
Cellular membrane affinity chromatography kit for drug discovery
用于药物发现的细胞膜亲和层析试剂盒
- 批准号:
10325006 - 财政年份:2021
- 资助金额:
$ 38万 - 项目类别:
SBIR Phase I: A New Class of Immobilized Metal Affinity Chromatography Resins
SBIR 第一阶段:一类新型固定金属亲和色谱树脂
- 批准号:
1746198 - 财政年份:2018
- 资助金额:
$ 38万 - 项目类别:
Standard Grant
Marine speciation of nickel using immobilized nickel affinity chromatography
使用固定镍亲和色谱法测定镍的海洋形态
- 批准号:
512537-2017 - 财政年份:2017
- 资助金额:
$ 38万 - 项目类别:
University Undergraduate Student Research Awards
I-Corps: Commercialization of Immobilized Metal Affinity Chromatography Resins Based on Nanomaterials
I-Corps:基于纳米材料的固定化金属亲和层析树脂的商业化
- 批准号:
1404605 - 财政年份:2014
- 资助金额:
$ 38万 - 项目类别:
Standard Grant
Antibody Purification via Affinity Chromatography that Utilizes the Unconventional Nucleotide Binding Site
利用非常规核苷酸结合位点通过亲和色谱法纯化抗体
- 批准号:
1263713 - 财政年份:2013
- 资助金额:
$ 38万 - 项目类别:
Continuing Grant
Development of multivalent DNA network based affinity chromatography diagnostics for isolating circulating tumour cells
开发基于多价 DNA 网络的亲和色谱诊断法,用于分离循环肿瘤细胞
- 批准号:
425749-2012 - 财政年份:2012
- 资助金额:
$ 38万 - 项目类别:
Postgraduate Scholarships - Master's
Next-Generation Affinity Chromatography with PEGylated Ligands
使用聚乙二醇化配体的新一代亲和色谱法
- 批准号:
1159886 - 财政年份:2012
- 资助金额:
$ 38万 - 项目类别:
Standard Grant
Immobilized zirconium ion affinity chromatography for specific enrichment of phosphoproteins
用于磷蛋白特异性富集的固定化锆离子亲和层析
- 批准号:
19560760 - 财政年份:2007
- 资助金额:
$ 38万 - 项目类别:
Grant-in-Aid for Scientific Research (C)
Accelerating drug discovery using frontal affinity chromatography/mass spectrometry
使用正面亲和色谱/质谱加速药物发现
- 批准号:
234753-2000 - 财政年份:2003
- 资助金额:
$ 38万 - 项目类别:
Collaborative Research and Development Grants