Novel Roles for Oncogenic SOX2 in Esophageal Squamous Cell Carcinoma

致癌性 SOX2 在食管鳞状细胞癌中的新作用

• 批准号: 9307770
• 负责人: Adam Joel Bass
• 金额: $ 38.49万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2015
• 资助国家: 美国
• 起止时间: 2015-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9307770
• 关键词: Address; Automobile Driving; Bass; Binding; Binding Sites; Biological Models; Cancer Etiology; Cell model; Chromosomes; Clustered Regularly Interspaced Short Palindromic Repeats; Complex; Cultured Cells; Data; Dependency; Development; Disease; ETV4 gene; Esophageal; Esophageal Squamous Cell Carcinoma; Gene Expression; Gene Silencing; Gene Targeting; Genes; Genetic; Genetic Transcription; Genome; Genomics; Goals; HRAS gene; Human; Impairment; In Vitro; Internal Ribosome Entry Site; Lead; Lung; Maintenance; Malignant Neoplasms; Malignant Squamous Cell Neoplasm; Malignant neoplasm of esophagus; Modeling; Mus; Nature; Oncogenes; Oncogenic; Oncoproteins; Pathogenesis; Patients; Physical Function; Physiological; Protein Isoforms; Public Health; Recurrence; Research; Role; Signal Transduction; Squamous Cell; Squamous Epithelium; Squamous cell carcinoma; Stem cells; Testing; The Cancer Genome Atlas; Therapeutic; Therapeutic Intervention; Transcription Factor AP-1; Transcription Factor Oncogene; Work; base; carcinogenesis; design; effective therapy; gene discovery; improved outcome; in vitro Model; in vivo; in vivo Model; insight; joint function; jun Oncogene; killings; novel; novel therapeutics; overexpression; precursor cell; programs; public health relevance; targeted treatment; therapeutic candidate; therapeutic target; tool; transcription factor; tumor

DESCRIPTION (provided by applicant): Esophageal squamous cell carcinoma (SCC) is a common and deadly disease that kills >400,000 people worldwide each year. A major barrier to improved outcomes is the lack of mechanistically-based (i.e., targeted) therapies. Through studying the role of the transcription factor oncogene SOX2 in esophageal SCC, we propose to advance our mechanistic understanding of this disease and identify new potential therapeutic vulnerabilities. We will follow upon our recent discovery that developmental transcription factor SOX2 is an oncogene subject to amplification or overexpression in the majority of esophageal SCCs. SOX2 is not only selectively subject to genomic amplification in SCCs but it is also essential for the normal development and proliferation of the esophageal squamous epithelium, suggesting a connection between the squamous cell carcinogenesis and transcriptional programs that maintain the squamous esophageal lineage. More recently, we found a novel physical and function interaction of SOX2 with the squamous transcription factor p63, specifically the oncogenic ΔNp63 isoform. Our discovery of this SOX2/p63 complex in SCC, we hypothesize, reveals a master transcriptional regulatory complex controlling survival and proliferative programs in the squamous lineage, programs frequently hijacked by SCCs. Additionally, our results suggest a new mechanism by which SOX2/p63 promotes SCC. We found that SOX2 and p63 jointly regulate factors promoting oncogenic signaling including ETV4, AP-1 transcription factors FOS and JUN and their activator, HRAS. Our results further suggest another mechanistic hypothesis for SOX2 activity in cancer, that AP-1 factors further interact with SOX2 to regulate gene expression in SCC. Our proposed focused inquiry into the activity of SOX2/p63 and SOX2/AP-1 provides an opportunity to identify squamous-specific SOX2 functions and mechanisms of SCC, leading to the identification of new candidate vulnerabilities in these tumors In Aim 1, we propose test our hypothesis that p63 is essential for the oncogenic function and activity of SOX2 in esophageal SCC carcinogenesis in vivo and in cultured cells. We will test the effects of loss of p63 upon SOX2 functions in both in vitro and in vivo models. Furthermore, we will jointly analyze experimental data on SOX2/p63 activity in SCC model systems with data on primary patient data from The Cancer Genome Atlas and systematically interrogate lead candidate SOX2 targets to identify novel dependencies in these cancers. In Aim 2 we propose to test our mechanistic hypotheses by charactering the interaction of SOX2 with AP-1 factors and delineating the joint functions of SOX2 with AP-1 factors in SCC. Overall, this research contributes to public health by greatly expanding our understanding on the mechanisms of an oncogene recurrently amplified a set of common and deadly cancers that have sparse effective therapies. This work is designed to specifically enhance understanding of the driving mechanisms of these cancers thus allowing us to ultimately develop more effective targeted therapies.

描述（由申请人提供）：食管鳞状细胞癌（SCC）是一种常见的致命疾病，每年在全世界造成超过40万人死亡。改善结果的一个主要障碍是缺乏基于机械的（即，有针对性的）治疗。通过研究转录因子癌基因SOX 2在食管SCC中的作用，我们建议推进我们对这种疾病的机制理解，并确定新的潜在治疗漏洞。我们将遵循我们最近的发现，即发育转录因子SOX 2是一种在大多数食管SCC中扩增或过表达的癌基因。SOX 2不仅在SCC中选择性地进行基因组扩增，而且对于食管鳞状上皮的正常发育和增殖也是必不可少的，这表明鳞状细胞癌发生与维持鳞状食管谱系的转录程序之间存在联系。最近，我们发现了SOX 2与鳞状转录因子p63，特别是致癌Δ Np 63亚型的一种新的物理和功能相互作用。我们假设，我们在SCC中发现的这种SOX 2/p63复合物揭示了一种控制鳞状细胞系存活和增殖程序的主转录调控复合物，这些程序经常被SCC劫持。此外，我们的研究结果提出了一种新的机制，SOX 2/p63促进SCC。我们发现SOX 2和p63共同调节促癌信号传导因子，包括ETV 4、AP-1转录因子FOS和JUN及其激活因子HRAS。我们的研究结果进一步提示了癌症中SOX 2活性的另一种机制假说，即AP-1因子进一步与SOX 2相互作用以调节SCC中的基因表达。我们提出的对SOX 2/p63和SOX 2/AP-1活性的集中调查提供了一个机会，以确定鳞状细胞特异性SOX 2功能和SCC机制，从而确定这些肿瘤中新的候选漏洞。在目的1中，我们提出测试我们的假设，即p63对SOX 2在体内和培养细胞中食管SCC致癌作用中的致癌功能和活性是必不可少的。我们将在体外和体内模型中测试p63缺失对SOX 2功能的影响。此外，我们将联合分析SCC模型系统中SOX 2/p63活性的实验数据和来自癌症基因组图谱的主要患者数据，并系统地询问主要候选SOX 2靶点，以确定这些癌症中的新依赖性。在目标2中，我们提出了测试我们的机制假设，通过描述SOX 2与AP-1因子的相互作用，并描绘SOX 2与AP-1因子在SCC中的联合功能。总的来说，这项研究极大地扩展了我们对癌基因反复放大的机制的理解，从而为公共卫生做出了贡献，这些癌基因导致了一系列常见且致命的癌症，而这些癌症缺乏有效的治疗方法。这项工作旨在特别增强对这些癌症驱动机制的理解，从而使我们能够最终开发出更有效的靶向治疗方法。