NANOG-positive cancer stem cells in liver oncogenesis induced by alcohol and HCV
NANOG-positive cancer stem cells in liver oncogenesis induced by alcohol and HCV
批准号:
10192606
负责人:
Keigo Machida
金额:
$37.13万
依托单位国家:
美国
项目类别:
财政年份:
2017
资助国家:
美国
项目状态:
已结题
起止时间:
2017-09-01 至 2023-05-31
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
中文摘要
摘要:由于转移性肝细胞癌的治疗成功率较低,导致的死亡人数持续上升。
临床干预。靶向癌症治疗消除了所有启动恶性肿瘤的干细胞(
TICS)至
防止复发和转移。肝细胞癌的发生与酒精和/或丙型肝炎病毒感染有关
常见于成分基因异常患者
复杂的SWI/SNF。基于CRISPR基因敲除的全基因组合成致死基因筛选
(壁虎)慢病毒文库在我们人源化小鼠模型的ARID1A突变细胞中鉴定出成分
(EZH2和EED)的多梳抑制复合体2(PRC2)。我们证明了多能性转录
因子NANOG通过抑制氧化作用代谢重新编程TIC以促进自我更新
磷酸化(OXPHOS)和激活脂肪酸氧化(FAO)。我们描述了酒精相关的
人肝细胞癌和酒精喂养的丙型肝炎病毒NS5A转基因(TG)小鼠在肝癌发展中的关键作用
Nanog是继TLR4激活之后的核心干细胞因子,是发生和发展所需的关键成分
抽搐的维护。
这些发现支持我们的假设,酒精介导的NANOG诱导和ARID1A突变
在酒精相关的肝细胞癌中协同产生化疗耐药药物。因此,目标是
ARID1a,a
染色质重塑
Nanog-PRC2复合体和粮农组织应消除TIC亚群。我们提出了三个具体目标。在……里面
目的1,我们将测试具有PRC2复合体的NANOG是否抑制OXPHOS并产生对索拉非尼耐药的TICE
酒精介导的人肝癌细胞中的突变ARID1A。在目标2中,我们将研究粮农组织的抑制如何抑制
对索拉非尼耐药突变ARID1A肿瘤的自我更新和促进细胞凋亡。在目标3中,我们将测试
索拉非尼联合PRC2/FAO抑制诱导细胞代谢重编程和细胞凋亡
肝细胞癌。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TICS
酒精西方饮食喂养和/或感染丙型肝炎病毒的FRG-Hu-Hep/HSC人源化小鼠和患者来源
异种移植。
总之,我们的基因分型肝细胞癌模型将简化用于疾病建模/毒性评估的临床试验
通过提供“在人性化小鼠身上进行的临床试验”。使用PDX和人性化的鼠标系统将提供
针对精确的合成致命性靶向策略的范式转换个性化医学的路径。适时的
根除因长期接触酒精而产生的耐药药物将是
有益且经济实惠
患有不治之症的病人。
这项提议将建立一种个性化的治疗方法
针对突变-ARID1A型肝癌的合成致死途径(PRC2)-NANOG复合体和粮农组织的战略。一个
成功的结果将导致范式的转变,从而促进个性化未来的发展
针对酒精相关性肝癌中出现的NANOG抽搐的治疗策略。
英文摘要
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.
期刊论文(1)
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会议论文
Nanog-positive cancer stem cells in and liver oncogenesis by alcohol and HCV
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批准号:7933535
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项目类别:
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资助金额:$38.09万
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财政年份:2009
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负责人:Keigo Machida
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Functional Dissection of EtOH-med Self-renew of Liver Tumor-Int Cells via TLR4
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资助金额:$19.87万
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海外基金