Validation of EP400 downstream effectors and potential therapeutic targets in Merkel cell carcinoma

项目摘要 人类致癌病毒在癌症研究中的作用 肿瘤病毒在人群中广泛传播，据报道导致20%的人类癌症。 DNA肿瘤病毒表达的病毒癌蛋白可以特异性地靶向宿主的中央淋巴结 蜂窝网络。即使在非病毒性癌症中，肿瘤病毒靶向的细胞蛋白也经常发生突变， 很可能是肿瘤发生的驱动因素。虽然癌症研究通常会被数十种 成千上万的乘客突变存在于癌症基因组中，紧凑的小DNA肿瘤病毒具有 为肿瘤学家提供了优势，使他们能够专注于少数病毒蛋白，以剖析基因调控网络， 癌James DeCaprio使用猿类鉴定视网膜母细胞瘤蛋白（RB 1）为第一个肿瘤抑制因子 多瘤病毒SV 40与其他三组一起。使用这种方法并持续取得成功， DeCaprio实验室通过鉴定SV 40等继续发现重要的细胞蛋白质 最近默克尔细胞多瘤病毒T抗原相关蛋白。使用SV 40大T抗原，DeCaprio 实验室鉴定了CUL 7、CUL 9、GLMN、FBWX 8、FAM 111 A、哺乳动物DREAM复合物和 MuvB-FoxM 1复合物。这些新的结合蛋白调节关键的细胞过程，有些是 与人类疾病有关。 最近，DeCaprio实验室专注于默克尔细胞多瘤病毒（MCPyV）及其 高侵袭性默克尔细胞癌（MCC）。虽然MCPyV可以感染90%以上的 在全球人口中，它通常不会引起任何症状。然而，MCPyV可以引起MCC， 比黑色素瘤致命几倍的疾病。考虑到这种广泛传播的病毒的致癌潜力， 重要的是，我们要了解人类多瘤病毒抗原的功能和他们的贡献， 癌 研究专家的活动/工作： 最近，我们对MCC的肿瘤发生机制有了新的认识。我们发现 MCPyV小肿瘤抗原（ST）将L-MYC（MYCL）募集到EP 400染色质复合物中，以驱动必需的 致癌过程我将继续为迪卡普里奥博士的研究项目的成功做出贡献。 （1）确定ST-MYCL-EP 400复合物的下游靶点， （2）确定MCC中的治疗靶点，并测试可能抑制肿瘤发生的小分子抑制剂。 MCPyV阳性MCC的存活力;（3）产生具有MCPyV靶向整合的MCC的小鼠模型 将肿瘤抗原导入小鼠安全港基因座。我的角色包括直接的科学贡献以及 在DeCaprio实验室对研究生和技术人员进行专门培训。

PROJECT SUMMARY The role of Human Oncogenic Viruses in Cancer Research Tumor viruses are widely spread in human population and are reported to cause 20% of human cancers. The DNA Tumor Viruses express viral oncoproteins that can specifically target the central nodes of host cellular networks. Cellular proteins targeted by tumor viruses are often mutated even in non-viral cancers and very likely to be driving factors of tumorigenesis. While cancer research is normally perplexed by tens of thousands of passenger mutations that reside in cancer genomes, compact small DNA tumor viruses have provided advantages for oncologists to focus on a few viral proteins to dissect gene regulatory networks in cancer. James DeCaprio identified Retinoblastoma Protein (RB1) as the first tumor suppressor using simian polyomavirus SV40 together with three other groups. Using this approach with continued success, the DeCaprio laboratory has continued to discover important cellular proteins by identifying SV40 and more recently Merkel cell polyomavirus T antigen associated proteins. Using SV40 Large T antigen, the DeCaprio laboratory identified CUL7, CUL9, GLMN, FBWX8, FAM111A, the mammalian DREAM complex and the MuvB-FoxM1 complex. These novel binding proteins regulate critical cellular processes, and some are involved in human diseases. More recently, the DeCaprio laboratory has focused on Merkel cell polyomavirus (MCPyV) and its contribution to the highly aggressive Merkel cell carcinoma (MCC). Although MCPyV can infect more than 90% of the global population, it typically does not cause any symptoms. However, MCPyV can cause MCC, a disease several times more lethal than melanoma. Given the oncogenic potential of this widespread virus, it is important for us to understand the functions of human polyomavirus viral antigens and their contribution to cancer. Research Specialist’s Activity/Effort: Recently, we gained novel insight into the mechanisms of tumorigenesis in MCC. We discovered that MCPyV small tumor antigen (ST) recruits L-MYC (MYCL) to the EP400 chromatin complex to drive essential oncogenic processes. I will continue to contribute to the success of Dr. DeCaprio’s research program in the following areas: (1) Identify downstream targets of ST-MYCL-EP400 complex that are required in tumorigenesis; (2) Identify therapeutic targets in MCC and test small molecule inhibitors that may inhibit the viability of MCPyV positive MCC; (3) Generate a mouse model of MCC with targeted integration of MCPyV tumor antigens into a mouse safe harbor locus. My roles include both direct scientific contributions as well as specific training of graduate students and technicians in the DeCaprio laboratory.