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

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)
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会议论文数量(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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