NANOG-positive cancer stem cells in liver oncogenesis induced by alcohol and HCV
NANOG阳性癌症干细胞在酒精和HCV诱导的肝癌发生中的作用
基本信息
- 批准号:10192606
- 负责人:
- 金额:$ 37.13万
- 依托单位:
- 依托单位国家:美国
- 项目类别:
- 财政年份:2017
- 资助国家:美国
- 起止时间:2017-09-01 至 2023-05-31
- 项目状态:已结题
- 来源:
- 关键词:ARID1A geneAddressAlcohol consumptionAlcohol-Related Hepatocellular CarcinomaAlcoholismAlcoholsApoptosisBAY 54-9085CRISPR screenCandidate Disease GeneCell DeathCellsCellular Metabolic ProcessCessation of lifeChIP-seqChemoresistanceChromatin Remodeling FactorChronicClinicalClinical TrialsClustered Regularly Interspaced Short Palindromic RepeatsCombined Modality TherapyComplexDNA Sequence AlterationDevelopmentDiseaseDisease modelDrug CombinationsDrug resistanceEZH2 geneEndotoxinsEpigenetic ProcessEvaluationFutureGenerationsGenesGenotypeHepatitis CHepatitis C virusHumanImmune systemInterventionInvestigationKnock-outKnockout MiceLentivirusLethal GenesLibrariesLiverMaintenanceMalignant NeoplasmsMediatingMetabolicMetastatic toMitochondriaModalityModelingMusMutationNeoplasm MetastasisOncogenicOutcomeOxidative PhosphorylationPPAR deltaPaperPathogenicityPathway interactionsPatientsPhenotypePolycombPrimary carcinoma of the liver cellsProductionPrognostic MarkerPropertyPublic HealthPublishingRefractoryRelapseResistanceRoleSWI/SNF Family ComplexStem Cell FactorStem cell pluripotencySystemTLR4 geneTestingTherapeuticTimeToxic effectTransgenic Micealcohol exposurebasecancer stem cellchemotherapychromatin remodelingcost effectivedesigndriver mutationfatty acid oxidationfeedingfunctional lossgenome wide screengenome-widegenotyped patientshepatocellular carcinoma cell linehumanized mousein vitro testinginhibitor/antagonistmouse modelmutantnovelpatient derived xenograft modelpersonalized medicinepluripotencypreclinical evaluationpreventresponsescreeningself-renewalstem-like cellsuccesstargeted cancer therapytargeted treatmenttranscription factortreatment strategytumortumorigenesiswestern diet
项目摘要
Abstract: Deaths due to metastatic hepatocellular carcinoma (HCC) continue to mount due to a low success of
clinical intervention. Targeted cancer therapy eliminates all malignant tumor-initiating stem-like cells (
TICs) to
prevent relapse and metastasis. Development of HCC is associated with alcohol and/or HCV infection and
frequently observed in patients with gene aberrations in component
complex SWI/SNF. Our synthetic lethal gene screening of genome-wide CRISPR-based knockout
(GeCKO)-lentivirus library in ARID1A-mutant cells of our humanized mouse models identified components
(EZH2 and EED) of polycomb suppressor complex 2 (PRC2). We demonstrated that pluripotency transcription
factor NANOG metabolically reprograms TICs to promote self-renewal via inhibition of oxidative
phosphorylation (OXPHOS) and activation of fatty acid oxidation (FAO). We characterized alcohol-associated
human HCCs and alcohol-fed, HCV NS5A transgenic (Tg) mice for HCC development and a critical role of
NANOG as a core stem cell factor following TLR4 activation as a crucial component needed for genesis and
maintenance of TICs.
These findings support our hypothesis that alcohol-mediated NANOG induction and ARID1A mutations
cooperatively generate chemoresistant TICs in alcohol-associated HCC. Therefore, targeting
ARID1A, a
of chromatin remodeling
NANOG-PRC2 complex and FAO should eliminate the TIC subpopulation. We propose three specific aims. In
Aim 1, we will test if NANOG with PRC2 complex inhibits OXPHOS and generates sorafenib-resistant TICs with
mutant ARID1A in alcohol mediated human HCCs. In Aim 2, we will examine how inhibition of FAO inhibit
self-renewal and promote apoprtosis in sorafenib-resistant mutant ARID1A tumors. In Aim 3, we will test if
combination therapy of sorafenib plus PRC2/FAO inhibition induces metabolic reprogramming and apoptosis in
HCC. We will test if targeting synthetic lethality genes (EZH2) eliminates TICs with ARID1A mutations by use of
alcohol Western diet-fed and/or HCV-infected FRG-hu-Hep/HSC humanized mice and patient-derived
xenograft.
In summary our genotyped HCC model will streamline clinical trials for disease modeling/toxicity evaluation
by offering “a clinical trial in a humanized mouse”. Use of PDX and humanized mouse systems will provide a
path to paradigm-shifting personalized medicine for an accurate synthetic lethality targeting strategy. The timely
eradication of chemoresistant TICs arising from chronic alcohol exposure will be
beneficial and cost-effective for
patients suffering from an otherwise incurable disease.
This proposal will establish a personalized therapy
strategy targeting a synthetic lethal pathway (PRC2)-NANOG complex and FAO in mutant-ARID1A HCCs. A
successful outcome will lead to a paradigm shift, thus facilitating the future development of personalized
treatment strategies targeted towards NANOG+ TICs appearing in alcohol-related HCC.
翻译后摘要:由于转移性肝细胞癌(HCC)的死亡继续安装由于低成功率,
临床干预。靶向癌症治疗消除了所有恶性肿瘤引发的干细胞样细胞(
TICs)至
防止复发和转移。HCC的发生与酒精和/或HCV感染有关,
常见于基因畸变的患者,
SWI/SNF复合体。我们基于全基因组CRISPR敲除的合成致死基因筛选
我们的人源化小鼠模型的ARID1A突变细胞中的(GeCKO)-慢病毒文库鉴定了组分
(EZH2和EED)。我们证明了多能性转录
NANOG因子代谢重编程TIC,通过抑制氧化应激促进自我更新。
磷酸化(OXPHOS)和脂肪酸氧化活化(FAO)。我们将酒精相关的
人肝癌和酒精喂养的HCV NS5A转基因(Tg)小鼠在肝癌发展中的关键作用
NANOG作为核心干细胞因子,在TLR4活化后作为发生和分化所需的关键组分,
维护TIC。
这些发现支持了我们的假设,即酒精介导的NANOG诱导和ARID1A突变
在酒精相关性HCC中协同产生耐药TIC。因此,针对
ARID1A,a
在染色质重塑
NANOG-PRC2综合体和粮农组织应消除TIC亚群。我们提出三个具体目标。在
目的1,我们将测试NANOG与PRC2复合物是否抑制OXPHOS并产生索拉非尼抗性TIC,
突变ARID1A在酒精介导的人HCC中的表达。在目标2中,我们将研究抑制FAO如何抑制
自我更新和促进索拉非尼耐药突变ARID1A肿瘤的细胞凋亡。在目标3中,我们将测试
索拉非尼加PRC2/FAO抑制的联合治疗诱导代谢重编程和细胞凋亡,
HCC。我们将测试靶向合成致死基因(EZH2)是否通过使用以下方法消除具有ARID1A突变的TIC:
酒精西方饮食喂养和/或HCV感染的FRG-hu-Hep/HSC人源化小鼠和患者来源的
异种移植
总之,我们的基因型HCC模型将简化疾病建模/毒性评价的临床试验
通过提供"在人源化小鼠中进行临床试验"。PDX和人源化小鼠系统的使用将提供
这是一条通往范式转变的个性化医疗的道路,以实现准确的合成致命性靶向策略。及时
根除由长期酒精暴露引起的耐药TIC,
有益且具有成本效益,
患有不治之症的病人。
这项建议将建立一个个性化的治疗
在muco-ARID1A HCC中靶向合成致死途径(PRC2)-NANOG复合物和FAO的策略。一
成功的结果将导致范式的转变,从而促进个性化的未来发展
针对酒精相关HCC中出现的NANOG + TIC的治疗策略。
项目成果
期刊论文数量(1)
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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Keigo Machida其他文献
Keigo Machida的其他文献
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{{ truncateString('Keigo Machida', 18)}}的其他基金
Nanog-positive cancer stem cells in and liver oncogenesis by alcohol and HCV
酒精和丙型肝炎病毒导致的 Nanog 阳性癌症干细胞和肝癌发生
- 批准号:
7933535 - 财政年份:2009
- 资助金额:
$ 37.13万 - 项目类别:
Nanog-positive cancer stem cells in and liver oncogenesis by alcohol and HCV
酒精和丙型肝炎病毒导致的 Nanog 阳性癌症干细胞和肝癌发生
- 批准号:
8133144 - 财政年份:2009
- 资助金额:
$ 37.13万 - 项目类别:
Nanog-positive cancer stem cells in and liver oncogenesis by alcohol and HCV
酒精和丙型肝炎病毒导致的 Nanog 阳性癌症干细胞和肝癌发生
- 批准号:
7800515 - 财政年份:2009
- 资助金额:
$ 37.13万 - 项目类别:
Nanog-positive cancer stem cells in and liver oncogenesis by alcohol and HCV
酒精和丙型肝炎病毒导致的 Nanog 阳性癌症干细胞和肝癌发生
- 批准号:
8318745 - 财政年份:2009
- 资助金额:
$ 37.13万 - 项目类别:
Nanog-positive cancer stem cells in and liver oncogenesis by alcohol and HCV
酒精和丙型肝炎病毒导致的 Nanog 阳性癌症干细胞和肝癌发生
- 批准号:
8516909 - 财政年份:2009
- 资助金额:
$ 37.13万 - 项目类别:
Research Project 3: Cell fate decision of liver tumor-initiating stem-like cells induced by alcohol
研究项目3:酒精诱导的肝肿瘤起始干细胞的细胞命运决定
- 批准号:
10551872 - 财政年份:1999
- 资助金额:
$ 37.13万 - 项目类别:
Research Project 3: Cell fate decision of liver tumor-initiating stem-like cells induced by alcohol
研究项目3:酒精诱导的肝肿瘤起始干细胞的细胞命运决定
- 批准号:
10322380 - 财政年份:1999
- 资助金额:
$ 37.13万 - 项目类别:
Research Project 3: Cell fate decision of liver tumor-initiating stem-like cells induced by alcohol
研究项目3:酒精诱导的肝肿瘤起始干细胞的细胞命运决定
- 批准号:
9886171 - 财政年份:
- 资助金额:
$ 37.13万 - 项目类别:
Functional Dissection of EtOH-med Self-renew of Liver Tumor-Int Cells via TLR4
通过 TLR4 进行 EtOH 诱导的肝肿瘤 Int 细胞自我更新的功能剖析
- 批准号:
8991273 - 财政年份:
- 资助金额:
$ 37.13万 - 项目类别:
Functional Dissection of EtOH-med Self-renew of Liver Tumor-Int Cells via TLR4
通过 TLR4 进行 EtOH 诱导的肝肿瘤 Int 细胞自我更新的功能剖析
- 批准号:
8597101 - 财政年份:
- 资助金额:
$ 37.13万 - 项目类别:
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