High-throughput multi-omic profiling of human oral squamous cell carcinoma (OSCC) to elucidate mechanisms of tumor initiation and progression

人类口腔鳞状细胞癌 (OSCC) 的高通量多组学分析，以阐明肿瘤发生和进展的机制

• 批准号: 9293122
• 负责人: Vinay Krishna Kartha
• 金额: $ 3.84万
• 依托单位: BOSTON UNIVERSITY (CHARLES RIVER CAMPUS)
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-04-01 至 2019-03-31
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9293122
• 关键词: Advanced Development; Automobile Driving; Behavior assessment; Bioinformatics; Biological Assay; Biological Markers; Biological Sciences; Boston; Cancerous; Carcinoma in Situ; Cell Line; Computational Science; Computer Analysis; Computer Simulation; Computing Methodologies; Coupled; Critical Thinking; DNA Methylation; Data; Data Set; Development; Diagnosis; Doctor of Philosophy; Ensure; Epigenetic Process; Epithelial; Epithelial Cell Proliferation; Event; Exhibits; Feedback; Gene Expression; Gene Expression Profile; Gene Expression Profiling; Gene Targeting; Genes; Genetic; Genetic Transcription; Genomics; Goals; Head and Neck Cancer; Health; Human; In Vitro; Institution; Link; Malignant - descriptor; Measures; Mentorship; Metabolic Pathway; Metabolism; Methods; MicroRNAs; Mild Dysplasia; Molecular; Mutation; Neoplasm Metastasis; Oral; Oral Stage; Oral cavity; Pathogenicity; Pathway interactions; Phenotype; Play; Premalignant; Proteins; RNA Interference; Regulation; Research; Research Personnel; Role; Savings; Signal Pathway; Signal Transduction; Somatic Mutation; Specimen; Survival Rate; Technology; Testing; The Cancer Genome Atlas; Therapeutic; Tissues; Tumorigenicity; Universities; Validation; Work; base; beta catenin; cancer genomics; career; cohort; computerized tools; data integration; differential expression; effective therapy; experimental analysis; experimental study; genome-wide; genomic tools; glycosylation; human tissue; in vivo; knock-down; malignant mouth neoplasm; migration; mouth squamous cell carcinoma; new therapeutic target; novel; oral cavity epithelium; public health relevance; response; skills; success; tool; transcriptome; transcriptome sequencing; treatment strategy; tumor initiation; tumor progression; tumorigenic

 DESCRIPTION (provided by applicant): The goal of this application is to identify biomarkers of oral squamous cell carcinoma (OSCC) initiation and progression to metastasis by integrating experimental and computational analysis approaches. Specifically, this study will investigate the role of a homeostatic cellular network consisting of the metabolic pathway of protein N-glycosylation, the Wnt/β-catenin and the Hippo/YAP signaling pathways in driving pro-tumorigenic activities in oral epithelia leading to the development and progression of OSCC. The elucidation of this network's key regulators and their downstream effectors offers the possibility to identify novel druggable targets in the OSCC pathogenic pathways and thus to advance the development of more effective and lasting OSCC therapies. Previous studies provide evidence that the interactions of this network are controlled by the N-glycosylation-regulating gene, DPAGT1, the Wnt pathway effector, β-catenin, and the Hippo pathway effector, YAP. The three factors are co-dependent in their expression and activity, and aberrant activation of the DPAGT1/β-catenin/YAP (glyco-βY) network promotes cancerous phenotypes. Of significance, the interrogation of genome-wide oral cancer datasets highlights increased activity of DPAGT1, β-catenin and YAP as a prominent feature of human OSCC. Activation of the glyco-βY signaling network is hypothesized to drive OSCC by promoting oral epithelial cell proliferation, survival and migration. Here, this hypothesis will be tested through the: (1) identification of gene targets significantly deregulated upon transcriptional inhibition of each of these effectors in OSCC cell lines; (2) definition of pro-tumorigenic gene expression signatures at different stages of primary human OSCC development, and elucidation of their role in driving OSCC to metastasis; (3) development of a novel computational method to associate genetic and epigenetic factors, which include somatic mutations and copy number alterations, DNA methylation and microRNAs, with gene expression signatures of OSCC pathogenic pathway activity. The experimental strategies will utilize a panel of human OSCC cell lines, human premalignant tissues, and human OSCC specimens. Unbiased global RNA-sequencing (RNASeq) interrogation using treated OSCC cell lines, and human tissue specimens at different stages of OSCC development will identify downstream effectors of the glyco-βY network, and will point to novel candidate targets which will be validated both experimentally, as well as computationally by interrogating large multi-omic oral cancer datasets. The deliverables of this application include: (i) validation of glyco-βY network involvement in OSCC development; (ii) identification of novel gene expression markers of human OSCC initiation and progression; (iii) development of a new integrative genomics tool that can identify candidate genetic and epigenetic drivers of signature-defined pathway activity in OSCC.

 描述（由申请人提供）：本申请的目的是通过整合实验和计算分析方法来鉴定口腔鳞状细胞癌（OSCC）开始和进展至转移的生物标志物。具体而言，本研究将探讨由蛋白质N-糖基化代谢途径、Wnt/β-catenin和Hippo/雅普信号通路组成的稳态细胞网络在驱动口腔上皮促肿瘤发生活性中的作用，从而导致OSCC的发生和进展。阐明该网络的关键调控因子及其下游效应物提供了在OSCC致病途径中识别新的可药物靶点的可能性，从而促进更有效和持久的OSCC治疗的发展。先前的研究提供了证据表明，该网络的相互作用是由N-糖基化调节基因DPAGT 1、Wnt途径效应子β-连环蛋白和Hippo途径效应子雅普控制的。这三种因子在其表达和活性方面是共同依赖的，并且DPAGT 1/β-连环蛋白/雅普（糖-βY）网络的异常激活促进癌表型。重要的是，对全基因组口腔癌数据集的询问突出了DPAGT 1、β-连环蛋白和雅普的活性增加作为人类OSCC的突出特征。糖-βY信号网络的激活被假设通过促进口腔上皮细胞增殖、存活和迁移来驱动OSCC。在此，将通过以下方式来检验这一假设：（1）鉴定在转录抑制每一个基因后显著失调的基因靶点， （2）确定人原发性口腔鳞癌发生发展不同阶段的促肿瘤基因表达特征，并阐明其在促进口腔鳞癌转移中的作用;（3）开发一种新的计算方法来关联遗传和表观遗传因素，包括体细胞突变和拷贝数改变，DNA甲基化和microRNA，具有OSCC致病途径活性的基因表达特征。实验策略将利用一组人类口腔鳞状细胞癌细胞系、人类癌前组织和人类口腔鳞状细胞癌标本。使用经处理的OSCC细胞系和OSCC发展不同阶段的人类组织标本进行无偏全局RNA测序（RNASeq）询问将鉴定glyco-βY网络的下游效应子，并将指向新的候选靶点，这些靶点将通过询问大型多组学口腔癌数据集进行实验和计算验证。该申请的可交付成果包括：（i）验证糖-βY网络参与OSCC发展;（ii）鉴定人类OSCC起始和进展的新基因表达标记物;（iii）开发新的整合基因组学工具，可以鉴定OSCC中签名定义的途径活性的候选遗传和表观遗传驱动因素。