Elucidating novel functions of cGAS in breast cancer

阐明 cGAS 在乳腺癌中的新功能

• 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
• 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

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.

人类免疫系统同时表现出特异性免疫和非特异性免疫(先天免疫)来防御 对抗病原体。CGAS/STING通路通过感知在先天免疫中发挥重要作用 源于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，某些癌症的刺痛消失会促进免疫- 抵抗。有趣的是，cGAS被发现可以促进细胞衰老，并且cGAS的低表达 与肺癌的不良预后有关。然而，cGAS失活是否以及如何对 肿瘤的发生，以及cGAS是否在癌症中发挥任何与生俱来的免疫独立功能仍然难以捉摸。 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。 导致乳腺癌患者死亡的主要原因是转移性疾病，而不是原发肿瘤。 目前还没有有效的治疗方法来治疗这种致命的疾病。理解分子 乳腺癌转移的机制可能导致治疗干预措施的发展 瞄准“阿喀琉斯的脚跟”这一疾病。 在这里，我们提供了几条证据来表明核cGAs发挥着一种新的功能，这是 不依赖于其在先天免疫中的典型功能，在抑制乳腺癌转移方面。首先，我们 与原发乳腺癌相比，转移性乳腺癌中观察到的核cGAS水平降低。第二，我们 发现cGAS在其NLS(核定位信号)中的乙酰化促进cGAS核浓缩和 这种核cGAs的缺失促进了乳腺癌的转移。第三，我们将cGAS鉴定为新的H4K8me1 具有抑制转移基因表达功能的阅读器。因此，H4K8me1结合缺陷 显著促进了乳腺癌的转移。鉴于我们对TCGA乳腺癌的信息学分析 患者表示，cGAS的总表达与转移和疾病分期无关，我们会 进一步确定是否可以减少cGAS乙酰化(这与核cGAS水平降低相关) 使用一组原发和转移性乳房作为转移性乳腺癌的预后标志 癌症患者的样本随处可得。此外，我们还将研究分子机制和生物学 CGAS在异种移植和基因治疗中抑制肿瘤转移的作用 小鼠模型，以及与这种调控失调相关的治疗脆弱性的初步探索 路径。总体而言，我们的研究对转移性乳腺癌以及新的 与乳腺癌复发相关的潜在见解。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方案，可能与肺的一个亚群相关 癌症也一样。