Elucidating novel functions of cGAS in breast cancer

阐明 cGAS 在乳腺癌中的新功能

基本信息

批准号：
10437847
负责人：
Pengda Liu
金额：
$ 35.57万
依托单位：
UNIV OF NORTH CAROLINA CHAPEL HILL
依托单位国家：
美国
项目类别：
财政年份：
2020
资助国家：
美国
起止时间：
2020-07-07 至 2025-06-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10437847
关键词：
3-Dimensional ATAC-seq Acetylation Acetyltransferase Amino Acid Motifs Bacterial Infections Binding Biochemical Genetics Biological Biological Assay Biophysics Breast Cancer Cell Breast Cancer Patient Breast cancer metastasis Cadherins Cell Aging Cell Nucleus Cessation of life ChIP-seq Chromatin Chromatin Structure Clinical Complex Cytoplasm DNA Data Deacetylase Deacetylation Development Disease Enzymes Epithelial Cells Exhibits Female Gene Expression Gene Silencing Genes Genetic Genetic Transcription Genomic DNA Genomics HDAC7 histone deacetylase Histones Human Immune Immune mediated destruction Immune system In Vitro Informatics Injections Innate Immune Response Knock-in Lead Malignant Neoplasms Malignant neoplasm of lung Mammary Neoplasms Mediating Metastatic breast cancer Metastatic to Mitochondrial DNA Molecular Natural Immunity Neoplasm Metastasis Nuclear Nuclear Import Nuclear Localization Signal Nucleosomes Outcome Pathway interactions Peptides Phenotype Play Post-Transcriptional Regulation Primary Neoplasm Prognostic Marker Proteomics Reader Regulation Role Sampling Signal Transduction Specimen Stimulator of Interferon Genes Tail Testing The Cancer Genome Atlas Therapeutic Therapeutic Intervention Tissue Microarray Tissues Veins Viral Virus Diseases Woman Xenograft procedure cancer recurrence cell motility cell type clinical prognosis cohort epithelial to mesenchymal transition genetic approach genetic regulatory protein genome-wide immune resistance in vivo insight lymph nodes mRNA Expression malignant breast neoplasm migration mortality mouse model novel novel therapeutics pathogen prevent sensor therapeutic development therapeutically effective transcriptome transcriptome sequencing tumor-immune system interactions tumorigenesis

项目摘要

The human immune system exhibits both specific and non-specific immunity (innate immunity) to defend against pathogens. The cGAS/STING pathway plays an essential role in innate immunity by sensing cytoplasmic DNA derived from viral or bacterial infection, and damaged genomic or mitochondrial DNA. Evading immune destruction is a hallmark of cancer, and loss of STING in certain cancers promotes immune- resistance. Interestingly, cGAS has been found to promote cellular senescence, and low cGAS expression correlates with poor outcome in lung cancer. However, whether and how cGAS inactivation is critical for tumorigenesis, and whether cGAS exerts any innate immunity-independent functions in cancer remain elusive. Breast cancer constitutes 25% of all cancers in women, making it the most common malignancy in females. Metastatic disease, rather than primary tumors, causes most death in breast cancer patients, and there is currently no effective therapeutic options available for this deadly disease. Understanding the molecular mechanisms governing breast cancer metastasis may lead to development of therapeutic interventions to target an “Achilles’ heel” this disease. Here we provide several lines of evidence to indicate that nuclear cGAS exerts a novel function, which is independent of its canonical function in innate immunity, in suppressing breast cancer metastasis. First, we observed levels of nuclear cGAS decreased in metastatic, compared with primary breast cancer. Second, we found that acetylation of cGAS in its NLS (nuclear localization signal) promoted cGAS nuclear enrichment and that loss of nuclear cGAS promoted breast cancer metastasis. Third, we identified cGAS as a novel H4K8me1 reader which functions to suppress metastatic gene expression. As a result, deficiency in H4K8me1 binding significantly facilitated breast cancer metastasis. Given that our informatics analyses in TCGA breast cancer patients indicated that total cGAS expression did not correlate with metastasis nor disease stage, we will further determine whether reduced cGAS acetylation (that correlates with reduced nuclear cGAS levels) can be used as a prognostic marker for metastatic breast cancer using a cohort of primary and metastatic breast cancer patient samples readily available. In addition, we will examine the molecular mechanisms and biological consequences underlying the metastasis suppressive function of cGAS using both xenograft and genetic murine models, along with the initial exploration of therapeutic vulnerabilities associated with this dysregulated pathway. Overall, our studies have significant implications for metastatic breast cancer, along with new potential insights relative to breast cancer recurrence. We are hopeful that our studies will facilitate the development of new therapeutic options for breast cancer patients, with potential relevance to a subset of lung cancer as well.

人体免疫系统表现出特异性和非特异性免疫（先天免疫）来防御 cGAS/STING 通路通过感知在先天免疫中发挥重要作用。来自病毒或细菌感染的细胞质 DNA，以及受损的基因组或线粒体 DNA。逃避免疫破坏是癌症的一个标志，某些癌症中 STING 的缺失会促进免疫提示，cGAS 被发现可促进细胞衰老，并且 cGAS 表达低。然而，cGAS 失活是否以及如何失活对于肺癌的不良预后至关重要。肿瘤发生以及 cGAS 是否在癌症中发挥任何与先天免疫无关的功能仍然难以捉摸。乳腺癌占女性所有癌症的25%，是女性最常见的恶性肿瘤。导致乳腺癌患者死亡的大多数是转移性疾病，而不是原发性肿瘤，并且目前还没有针对这种致命疾病的有效治疗方案。控制乳腺癌转移的机制可能会导致治疗干预措施的发展针对这种疾病的“致命弱点”。在这里，我们提供了几条证据来表明核 cGAS 发挥着一种新功能，即独立于其在先天免疫中的典型功能，在抑制乳腺癌转移方面。与原发性乳腺癌相比，我们观察到转移性乳腺癌的核 cGAS 水平降低。发现 cGAS 在其 NLS（核定位信号）中的乙酰化促进了 cGAS 核富集，第三，我们将 cGAS 鉴定为一种新型 H4K8me1。阅读器具有抑制转移基因表达的功能，因此 H4K8me1 结合缺陷。鉴于我们对 TCGA 乳腺癌的信息学分析，显着促进了乳腺癌转移。患者表示总 cGAS 表达与转移或疾病阶段无关，我们将进一步确定是否可以减少 cGAS 乙酰化（与核 cGAS 水平降低相关）使用一组原发性和转移性乳腺癌作为转移性乳腺癌的预后标志物此外，我们还将研究癌症患者的分子机制和生物学机制。使用异种移植和遗传的 cGAS 转移抑制功能的后果小鼠模型，以及与这种失调相关的治疗脆弱性的初步探索总体而言，我们的研究对转移性乳腺癌以及新的癌症具有重要意义。我们希望我们的研究能够促进乳腺癌复发的潜在相关见解。为乳腺癌患者开发新的治疗方案，可能与肺的一个子集相关癌症也是如此。