Elucidating novel functions of cGAS in breast cancer

阐明 cGAS 在乳腺癌中的新功能

• 批准号: 10212348
• 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
• 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/10212348
• 关键词: 3-Dimensional; ATAC-seq; Acetylation; Acetyltransferase; Amino Acid Motifs; Antiviral Agents; 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; Prognosis; 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; 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

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.

人类免疫系统表现出特异性和非特异性免疫（先天免疫），以防御 对抗病原体cGAS/STING通路通过感测免疫原性在先天免疫中起着重要作用。 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，在某些癌症中STING的缺失会促进免疫- 阻力有趣的是，已经发现cGAS促进细胞衰老，并且降低cGAS表达。 与肺癌预后不良相关。然而，cGAS失活是否以及如何对于 cGAS在肿瘤发生中的作用以及cGAS是否在癌症中发挥任何先天免疫非依赖性功能仍然是难以捉摸的。 乳腺癌占女性所有癌症的25%，使其成为女性最常见的恶性肿瘤。 转移性疾病，而不是原发性肿瘤，导致大多数乳腺癌患者死亡， 目前没有有效的治疗选择可用于这种致命的疾病。了解分子 控制乳腺癌转移的机制可能导致治疗干预的发展， 针对“阿喀琉斯之踵”这种疾病。 在这里，我们提供了几条证据，表明核cGAS发挥了一种新的功能， 独立于其在先天免疫中的典型功能，在抑制乳腺癌转移中。一是 与原发性乳腺癌相比，转移性乳腺癌中观察到的核cGAS水平降低。二是 发现cGAS在其NLS（核定位信号）中的乙酰化促进cGAS核富集， 核cGAS的缺失促进了乳腺癌转移。第三，我们将cGAS鉴定为新的H4 K8 me 1 阅读器，其功能是抑制转移基因表达。因此，H4 K8 me 1结合缺陷 显著促进乳腺癌转移。鉴于我们对TCGA乳腺癌的信息学分析 患者表明总cGAS表达与转移或疾病分期无关，我们将 进一步确定降低的cGAS乙酰化（其与降低的核cGAS水平相关）是否可以被 使用原发性和转移性乳腺癌的队列，作为转移性乳腺癌的预后标志物 癌症患者的样本很容易获得。此外，我们将研究分子机制和生物学 使用异种移植物和基因治疗的cGAS的转移抑制功能的潜在后果 小鼠模型，沿着与这种失调相关的治疗脆弱性的初步探索， 通路总的来说，我们的研究对转移性乳腺癌有重要意义，沿着新的 对乳腺癌复发的潜在见解。我们希望我们的研究将有助于 为乳腺癌患者开发新的治疗选择，与肺癌的一个子集可能相关 癌症也是。