Antagonistic role of ARF and ADAR1 in triple-negative breast cancer

ARF和ADAR1在三阴性乳腺癌中的拮抗作用

基本信息

批准号：
10571897
负责人：
Jason Weber
金额：
$ 41.2万
依托单位：
WASHINGTON UNIVERSITY
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：
2022-02-14 至 2027-01-31
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10571897
关键词：
ADAR1 Acceleration Agonist Alleles Antiviral Response Binding Binding Proteins Biochemical Biological Markers Breast Cancer Cell Breast Cancer cell line Breast Epithelial Cells Cancer cell line Cell Death Cell Nucleolus Cells Cellular biology Cessation of life Chronic Clinical Complex DNA Data Deaminase Dependence Environment Enzymes Epithelium Etiology Gene Mutation Gene Targeting Genes Genetic Human IFNAR1 gene Immune In Vitro Interferon Activation Interferon Type I Interferons Laboratories MDM2 gene Malignant Neoplasms Mammary Neoplasms Molecular Mutation Neoplasm Metastasis Oncogenic Pathway interactions Patient-derived xenograft models of breast cancer Patients Penetration Phenotype Production Proteins Proto-Oncogenes Publishing RNA Repression Research Research Personnel Resistance Role STING agonists Signal Transduction Stress TP53 gene Testing Therapeutic Therapeutic Agents Titrations Tumor Suppressor Proteins Tumor-Infiltrating Lymphocytes Work anti-tumor immune response anticancer research effective therapy functional loss genetic signature immune cell infiltrate in vivo innovation insight interferon alpha receptor knock-down malignant breast neoplasm mutant neoplastic cell novel novel strategies patient response peptidomimetics prevent programmed cell death ligand 1 protein expression protein function response stem therapeutic target triple-negative invasive breast carcinoma tumor tumor microenvironment tumorigenesis

项目摘要

PROJECT SUMMARY Triple-negative breast cancer (TNBC) has remained a considerable clinical challenge due to the lack of efficacious genetic targets. We need unique effective therapies and accurate biomarkers that can be used to predict patient responses in TNBC. We find that the ARF tumor suppressor is lost alongside p53 mutation in 60% of TNBC. Potentially stemming from the dual loss of ARF and p53, we have observed that type I IFN signaling is elevated in TNBC. We show that this IFN production is being kept in check by the ADAR1 enzyme. Notably, we discovered that ADAR1 is a novel binding partner for ARF. The central premise of this proposal is that the novel ARF-ADAR1 interaction provides key insights into how these two proteins function in the etiology of TNBC. The research application focuses on the role of this interaction in regulating the type I interferon response and sensitizing TNBC cells to cell death and immune recognition. The overarching hypothesis of the proposed research is that loss of ARF and p53 results in elevated type I IFN signaling and sensitizes cells to ADAR1 depletion. In Aim 1, we will define the functional interaction of ARF and ADAR1. In the absence of functional p53, ARF protein expression is induced. In this setting, we find that ARF can fully titrate all the cellular ADAR1 into ARF complexes. We will test the hypothesis that ARF mechanistically traps ADAR1 in the nucleolus to prevent ADAR1 from repressing the type I interferon pathway. In Aim 2, we present data that TNBC cells are sensitive to ADAR1 depletion. Importantly, this sensitivity is dependent on type I interferon signaling. We will test the hypothesis that activation of IFN production and signaling will combine with ADAR1 depletion to produce synthetic lethality in vitro and in vivo. We will utilize both agonists of the IFN pathway and synthetic ARF peptide mimics. In Aim 3, we will assess how the ARF-ADAR1 interaction influences the tumor microenvironment. While type I IFN release is a major component of the anti-viral response, chronic IFN- release by tumor cells can both alter the local immune environment and expression of PD-L1 on tumor cells. We will test the hypothesis that hyperactivation of the type I IFN pathway by ADAR depletion will result in gains in tumor infiltrating lymphocytes and elicit an anti-tumor immune response that will prevent metastasis. These studies are paramount to informing new approaches in treating TNBC through activation of IFN signaling in the tumor microenvironment.

项目摘要由于三阴性乳腺癌（TNBC），由于缺乏有效的遗传靶标。我们需要独特的有效疗法和准确的生物标志物可以用来预测TNBC中的患者反应。我们发现ARF肿瘤抑制剂在60％的TNBC中，与P53突变一起丢失。可能是由于ARF的双重损失而导致的和p53，我们已经观察到I型IFN信号在TNBC中升高。我们证明了这个IFN ADAR1酶正在检查生产。值得注意的是，我们发现Adar1是 ARF的新颖绑定伙伴。该提议的主要前提是小说Arf-Adar1 相互作用提供了有关这两种蛋白在TNBC病因中如何发挥作用的关键见解。这研究申请的重点是这种相互作用在调查I类型干扰素中的作用对细胞死亡和免疫识别的反应和敏感。总体拟议研究的假设是ARF和p53的丧失导致I型IFN升高对ADAR1部署的信号传导和敏感细胞。在AIM 1中，我们将定义ARF和ADAR1的功能相互作用。在没有功能的情况下 p53，ARF蛋白表达被诱导。在这种情况下，我们发现ARF可以完全滴定所有细胞ADAR1进入ARF复合物。我们将测试ARF机械陷阱的假设核仁中的ADAR1防止ADAR1抑制I型干扰素途径。目标 2，我们介绍了TNBC单元对ADAR1部署敏感的数据。重要的是，这种敏感性取决于I型干扰素信号传导。我们将检验以下假设生产和信号传导将与ADAR1部署相结合，在体外产生合成的致死性和体内。我们将利用IFN途径的两种激动剂和合成的Arf Peppery Mimics。在AIM 3中，我们将评估ARF-ADAR1相互作用如何影响肿瘤微环境。而I型IFN释放是抗病毒反应的主要组成部分，而慢性IFN-释放肿瘤细胞既可以改变局部免疫环境和肿瘤上PD-L1的表达细胞。我们将测试以下假设：ADAR部署的I型IFN途径的过度激活将导致肿瘤浸润淋巴细胞的增长，并引起抗肿瘤免疫反应将防止转移。这些研究对于告知治疗的新方法至关重要 TNBC通过激活肿瘤微环境中的IFN信号传导。