System-Level Analyses of Multi-Omics Data to Reveal Mechanisms of Head & Neck Cancer

多组学数据的系统级分析揭示头部机制

• 批准号: 10593974
• 负责人: STEFANO MONTI
• 金额: $ 43.49万
• 依托单位: BOSTON UNIVERSITY MEDICAL CAMPUS
• 依托单位国家: 美国
• 财政年份: 2022
• 资助国家: 美国
• 起止时间: 2022-03-17 至 2025-01-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10593974
• 关键词: Adopted; Automobile Driving; Behavior; Binding; Binding Proteins; Bioconductor; Bioinformatics; Biological; Cancer cell line; Carcinoma in Situ; Cell Proliferation; Cells; Communities; Computer Analysis; Cyclic AMP; DNA Sequence Alteration; Data; Data Analyses; Data Set; Death Rate; Development; Diagnosis; Disease; Elements; Encyclopedias; Erythroplasia; Evaluation; FRAP1 gene; Gene Expression; Genes; Genetic; Genetic Transcription; Goals; Head Cancer; Head and Neck Squamous Cell Carcinoma; Human; Human Papillomavirus; In Vitro; Laboratories; Lesion; Leukoplakia; Link; Malignant - descriptor; Malignant Neoplasms; Maps; Mediating; Metastatic Neoplasm to Lymph Nodes; Methods; Modeling; Molecular; Mouth Neoplasms; Multiomic Data; Mus; Mutation; Neck Cancer; Neoplasm Metastasis; Network-based; Nuclear; Oncogenic; Oral Stage; Pathway interactions; Patients; Pattern; Phenotype; Play; Population; Premalignant Cell; Proteomics; Reporting; Research; Research Personnel; Resources; Role; Signal Pathway; Signal Transduction; Squamous cell carcinoma; Survival Rate; Symptoms; System; Taxonomy; The Cancer Genome Atlas; Therapeutic; Time; Tissues; Variant; Visualization; advanced disease; beta catenin; cancer initiation; cancer stem cell; candidate identification; candidate validation; cell type; disease diagnosis; draining lymph node; epithelial to mesenchymal transition; experimental study; gene regulatory network; histone acetyltransferase; human data; human tissue; improved; in silico; in vivo Model; inhibitor; insight; malignant mouth neoplasm; methylomics; mouth squamous cell carcinoma; multiple omics; novel; novel therapeutics; open source; oral lesion; pharmacologic; portability; premalignant; rational design; resistance mechanism; response; single cell analysis; single-cell RNA sequencing; small molecule; therapeutic target; therapy resistant; tool; trait; transcriptome sequencing; tumor; tumor initiation; tumor progression; web portal

Head and neck squamous cell carcinoma (HNSCC) is a devastating disease with an overall 5-year survival rate of only ~60%. In part, this high death rate is a result of late disease diagnosis, often with regional lymph node metastasis. Recent studies, including The Cancer Genome Atlas (TCGA), and the Cancer Cell Line Encyclopedia (CCLE), mapped genomic alterations in a variety of cancers, and are beginning to provide insights into the dysregulated signals contributing to the onset and progression of HNSCC, but there has been only modest improvement in therapeutic strategies. This lack of progress is partly due to a lack of mechanistic understanding of the signals that drive malignant transformation. Prior and ongoing studies carried out in our laboratories have identified multiple homeostatic pathways whose deregulation contributes to HNSCC HPV(-) initiation, development and progression. In particular, we have shown that pharmacologic inhibition of the interaction between 𝛽𝛽-catenin and the histone acetyltransferase cAMP-responsive element binding (CREB)-binding protein (CBP) inhibits HNSCC cell proliferation and CSC phenotypes, and reduces invasive traits. Conversely, we showed that elevated β-catenin/CBP signaling in primary HNSCC tumors was associated with tumor progression and poor patient survival. We also showed a strong association between WNT/𝛽𝛽-catenin, the oncogenic activity of the paralogous transcriptional regulators YAP and TAZ (YAP/TAZ), and of mTOR, suggesting interactions between these pathways. Thus, our proposal seeks to elucidate, through computational approaches, the molecular links between somatic variation, the activity of selected homeostatic pathways (𝛽𝛽-catenin/CBP, TAZ/YAP, mTOR and others), and EMT and CSC phenotypes in early and advanced stages of HNSCC. To achieve this goal, we will perform integrative analyses of public multi-omics datasets from human and mouse, leveraging our newly developed methods of taxonomy discovery and gene regulatory network (GRN) inference. Application of these methods will allow us to identify important network hubs and regulators, and how their connectivity changes in response to perturbation or between phenotypic groups and disease stages. The hypotheses generated will be validated in in-vitro and in-vivo models we have developed in our laboratories. The results of our analyses will support the identification of novel candidate drivers of the disease amenable to therapeutic targeting. Three aims are thus proposed. First, we will analyze publicly available multi-omics datasets from human HNSCC, including bulk and single-cell RNAseq profiles, proteomics and methylomics profiles, and paired somatic copy number alterations (SCNAs) and mutations. Second, we will analyze bulk- and sc-RNAseq profiles from premalignant lesions in mouse and human, including profiles from mice treated with small molecule 𝛽𝛽-catenin/CBP inhibitors. Finally, we will share all our tools and results through well-documented Bioconductor packages and interactive web-based portals, which will allow other investigators to use the generated resources in their research.

头颈部鳞状细胞癌（HNSCC）是一种具有破坏性的疾病，总体生存期为5年 率仅为60%。在某种程度上，这种高死亡率是由于疾病诊断较晚，通常伴有局部淋巴结转移。 结转移最近的研究，包括癌症基因组图谱（TCGA）和癌细胞系 百科全书（CCLE）绘制了各种癌症的基因组变异，并开始提供 对导致HNSCC发病和进展的失调信号的深入了解，但已经有 只有适度的改善治疗策略。这种缺乏进展的部分原因是缺乏机械性的 了解导致恶性转化的信号。 在我们的实验室中进行的先前和正在进行的研究已经确定了多种稳态途径， HNSCC HPV（-）的发生、发展和进展与HNSCC HPV（-）的发生、发展和进展有关。我们特别 显示了对β-连环蛋白和组蛋白乙酰转移酶之间相互作用的药理学抑制 cAMP反应元件结合蛋白（CREB）抑制HNSCC细胞增殖和CSC 表型，并减少入侵性状。相反，我们发现，β-catenin/CBP信号通路的升高， 原发性HNSCC肿瘤与肿瘤进展和患者存活率低相关。我们还展示了一个 WNT/β-catenin之间的强关联，旁系同源转录调节因子的致癌活性 雅普和TAZ（雅普/TAZ），以及mTOR，表明这些途径之间的相互作用。 因此，我们的建议试图通过计算方法阐明， 体细胞变异，所选稳态途径的活性（β-连环蛋白/CBP、TAZ/雅普、mTOR等）， 以及HNSCC早期和晚期的EMT和CSC表型。为了实现这一目标，我们将 综合分析来自人类和小鼠的公共多组学数据集，利用我们新开发的 分类发现和基因调控网络（GRN）推理方法。应用这些方法 将使我们能够确定重要的网络枢纽和监管机构，以及它们的连接如何响应变化 到扰动或表型组和疾病阶段之间。将验证生成的假设 在我们实验室开发的体外和体内模型中。我们的分析结果将支持 鉴定适合治疗靶向的疾病的新候选驱动因素。三个目标是 因此提出。首先，我们将分析来自人类HNSCC的公开可用的多组学数据集，包括 批量和单细胞RNAseq图谱、蛋白质组学和甲基化组学图谱以及配对体细胞拷贝数 变异（SCNA）和突变。第二，我们将分析癌前病变的bulk和sc-RNAseq图谱， 在小鼠和人中的损伤，包括来自用小分子β-连环蛋白/CBP抑制剂治疗的小鼠的谱。 最后，我们将通过记录良好的Bioconductor软件包和互动软件包分享我们所有的工具和结果。 基于网络的门户网站，这将使其他研究人员在他们的研究中使用生成的资源。