Novel Roles for Oncogenic SOX2 in Esophageal Squamous Cell Carcinoma

描述（申请人提供）：食管鳞状细胞癌（SCC）是一种常见的致命疾病，每年在世界范围内造成40万人死亡。改善结果的一个主要障碍是缺乏基于机械的（即靶向的）治疗。通过研究转录因子癌基因SOX2在食管鳞状细胞癌中的作用，我们建议进一步了解这种疾病的机制，并发现新的潜在治疗漏洞。我们将继续我们最近的发现，即发育转录因子SOX2在大多数食管SCCs中是一个扩增或过表达的致癌基因。SOX2不仅在SCCs中选择性地受到基因组扩增的影响，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，这表明鳞状细胞癌变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SOX2与鳞状转录因子p63的一种新的物理和功能相互作用，特别是致癌的ΔNp63亚型。我们在SCC中发现的SOX2/p63复合体，我们假设，揭示了一个控制鳞状谱系中生存和增殖程序的主要转录调控复合体，这些程序经常被SCC劫持。此外，我们的研究结果表明SOX2/p63促进SCC的新机制。我们发现SOX2和p63共同调控促进致癌信号传导的因子，包括ETV4、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出了SOX2在癌症中活性的另一种机制假设，即AP-1因子进一步与SOX2相互作用以调节SCC中的基因表达。我们提出的对SOX2/p63和SOX2/AP-1活性的重点研究为鉴定鳞状特异性SOX2的功能和SCC机制提供了机会，从而鉴定这些肿瘤的新候选脆弱性。在Aim 1中，我们提出验证我们的假设，即p63对于SOX2在体内和培养细胞中食道SCC癌变中的致癌功能和活性至关重要。我们将在体外和体内模型中测试p63缺失对SOX2功能的影响。此外，我们将联合分析SCC模型系统中SOX2/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SOX2的主要候选靶点，以确定这些癌症的新依赖性。在Aim 2中，我们提出通过表征SOX2与AP-1因子的相互作用并描述SOX2与AP-1因子在SCC中的联合功能来验证我们的机制假设。总的来说，这项研究通过极大地扩展我们对致癌基因的机制的理解，为公共卫生做出了贡献，这些致癌基因反复放大了一系列常见和致命的癌症，而这些癌症缺乏有效的治疗方法。这项工作旨在加强对这些癌症驱动机制的理解，从而使我们最终能够开发出更有效的靶向治疗方法。

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.