Targeting the LIFR-LCN2 pathway to improve liver cancer therapy

靶向 LIFR-LCN2 通路改善肝癌治疗

基本信息

  • 批准号:
    10583188
  • 负责人:
  • 金额:
    $ 48.01万
  • 依托单位:
  • 依托单位国家:
    美国
  • 项目类别:
  • 财政年份:
    2023
  • 资助国家:
    美国
  • 起止时间:
    2023-01-01 至 2027-12-31
  • 项目状态:
    未结题

项目摘要

PROJECT SUMMARY/ABSTRACT Iron is vital for many physiological processes, but excessive iron causes toxicity. Dysregulated iron homeostasis (either iron deficiency or overload) is a harbinger of pathological conditions. The liver stores iron in hepatocytes and is the major organ that controls systemic iron homeostasis. Liver cancer, primarily hepatocellular carcinoma (HCC), is highly lethal with limited treatment options and no biomarkers to predict therapy response. Leukemia inhibitory factor receptor (LIFR) is frequently downregulated in human HCC; however, in vivo and genetic studies of LIFR’s functions in liver cancer development and therapy response were lacking. Recently, by constructing and characterizing hepatocyte-specific and inducible Lifr-knockout mice, we found that loss of Lifr promoted liver tumorigenesis and conferred resistance to sorafenib-induced ferroptosis, a non-apoptotic type of cell death characterized by the iron-dependent accumulation of lipid hydroperoxides. Our data also pointed to a role for LIFR in inhibiting NF-κB signaling in the liver, which in turn downregulates lipocalin 2 (LCN2), an iron- sequestering cytokine. In parallel, our data revealed that in oncogene-induced liver tumors, overexpression of LIFR increased, while knockout of Lifr decreased CD8+ T cell infiltration, which may be mediated by LCN2- dependent downregulation of iron levels, viability, and proliferation of T cells. Altogether, these data support a hypothesis that loss or downregulation of LIFR in liver cancer leads to upregulation of LCN2, which on one hand confers resistance to ferroptosis on liver tumor cells, and on the other hand, deprives T cells of iron that is essential for T cell viability, proliferation, and effector function; both mechanisms contribute to liver cancer progression and therapy resistance. In the proposed work, we will elucidate the molecular mechanisms by which LIFR inhibits NF-κB signaling in liver cells (Specific Aim 1). Further, we will investigate whether LCN2 can serve as a therapeutic target for enhancing sorafenib efficacy in HCC (Specific Aim 2). Finally, we will study whether LIFR or therapeutic LCN2 neutralization can sensitize HCC to immunotherapy (Specific Aim 3). Genetically engineered mouse models, Sleeping Beauty transposon-mediated oncogene-induced liver cancer models, and HCC patient-derived xenograft models will be used to study the therapeutic potential and mechanisms of action of two novel drug combinations, which will illuminate how to improve liver cancer therapy by targeting an iron- sequestering pathway. We envision that low LIFR expression and high LCN2 expression could be used to select HCC patients who will likely benefit from the combination therapy with the LCN2-neutralizing antibody plus sorafenib or immune checkpoint inhibitors.
项目总结/摘要 铁对许多生理过程至关重要,但过量的铁会导致毒性。铁稳态失调 (铁缺乏或超负荷)是病理状况的预兆。肝脏将铁储存在肝细胞中 并且是控制全身铁稳态的主要器官。肝癌,主要是肝细胞癌 (HCC)是高度致命的,治疗选择有限,没有生物标志物来预测治疗反应。白血病 抑制因子受体(LIFR)在人HCC中经常下调;然而,在体内和遗传研究中, 缺乏LIFR在肝癌发生发展和治疗反应中的作用。最近,通过构建 通过对肝细胞特异性和可诱导的Lifr基因敲除小鼠的研究,我们发现, 肿瘤发生,并对索拉非尼诱导的铁凋亡(一种非凋亡类型的细胞死亡)产生抗性 其特征在于脂质氢过氧化物的铁依赖性积累。我们的数据还指出, LIFR抑制肝脏中NF-κB信号传导,进而下调脂质运载蛋白2(LCN 2),一种铁- 隔离细胞因子。同时,我们的数据显示,在癌基因诱导的肝癌中, LIFR增加,而LIFR敲除减少CD 8 + T细胞浸润,这可能是由LCN 2-介导的。 铁水平、存活力和T细胞增殖的依赖性下调。这些数据支持了 假设肝癌中LIFR的缺失或下调导致LCN 2的上调,这一方面 赋予肝肿瘤细胞对铁凋亡的抵抗力,另一方面,剥夺T细胞的铁, 对T细胞活力、增殖和效应功能至关重要;这两种机制都有助于肝癌 进展和治疗抵抗。在拟议的工作中,我们将阐明分子机制, LIFR抑制肝细胞中的NF-κB信号传导(特异性目的1)。此外,我们将研究LCN 2是否可以服务于 作为增强索拉非尼在HCC中的疗效的治疗靶点(具体目标2)。最后,我们将研究 LIFR或治疗性LCN 2中和可使HCC对免疫疗法敏感(特异性目的3)。基因 工程小鼠模型,睡美人转座子介导的癌基因诱导的肝癌模型,和 HCC患者来源的异种移植模型将用于研究治疗潜力和作用机制 两种新型药物组合,这将阐明如何通过靶向铁改善肝癌治疗, 螯合途径我们设想,低LIFR表达和高LCN 2表达可用于选择 可能受益于LCN 2中和抗体联合治疗的HCC患者 索拉非尼或免疫检查点抑制剂。

项目成果

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Li Ma其他文献

Effect of capital constraints on the risk preference behavior of commercial banks
资本约束对商业银行风险偏好行为的影响

Li Ma的其他文献

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{{ truncateString('Li Ma', 18)}}的其他基金

Statistical modeling of cross-sample variation and learning of latent structures in microbiome sequencing data
跨样本变异的统计建模和微生物组测序数据中潜在结构的学习
  • 批准号:
    10688000
  • 财政年份:
    2020
  • 资助金额:
    $ 48.01万
  • 项目类别:
Statistical modeling of cross-sample variation and learning of latent structures in microbiome sequencing data
跨样本变异的统计建模和微生物组测序数据中潜在结构的学习
  • 批准号:
    10263932
  • 财政年份:
    2020
  • 资助金额:
    $ 48.01万
  • 项目类别:
Statistical modeling of cross-sample variation and learning of latent structures in microbiome sequencing data
跨样本变异的统计建模和微生物组测序数据中潜在结构的学习
  • 批准号:
    10468838
  • 财政年份:
    2020
  • 资助金额:
    $ 48.01万
  • 项目类别:
Epithelial-mesenchymal transition regulators in radioresistance and DNA repair
放射抗性和 DNA 修复中的上皮-间质转化调节因子
  • 批准号:
    9095257
  • 财政年份:
    2014
  • 资助金额:
    $ 48.01万
  • 项目类别:
Epithelial-mesenchymal transition regulators in radioresistance and DNA repair
放射抗性和 DNA 修复中的上皮-间质转化调节因子
  • 批准号:
    8751065
  • 财政年份:
    2014
  • 资助金额:
    $ 48.01万
  • 项目类别:
Regulation of metastasis and epithelial-mesenchymal transition by microRNAs
microRNA对转移和上皮间质转化的调节
  • 批准号:
    8511590
  • 财政年份:
    2012
  • 资助金额:
    $ 48.01万
  • 项目类别:
Non-coding RNA functions in tumor metastasis
非编码RNA在肿瘤转移中的作用
  • 批准号:
    10311482
  • 财政年份:
    2012
  • 资助金额:
    $ 48.01万
  • 项目类别:
Non-coding RNA functions in tumor metastasis
非编码RNA在肿瘤转移中的作用
  • 批准号:
    10531262
  • 财政年份:
    2012
  • 资助金额:
    $ 48.01万
  • 项目类别:
Regulation of metastasis and epithelial-mesenchymal transition by microRNAs
microRNA对转移和上皮间质转化的调节
  • 批准号:
    8676742
  • 财政年份:
    2012
  • 资助金额:
    $ 48.01万
  • 项目类别:
Regulation of metastasis and epithelial-mesenchymal transition by microRNAs
microRNA对转移和上皮间质转化的调节
  • 批准号:
    8851531
  • 财政年份:
    2012
  • 资助金额:
    $ 48.01万
  • 项目类别:

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