Identification of Novel Oncogenic Signaling Pathways using Viral Perturbations

项目摘要 默克尔细胞癌(MCC)是一种原发性皮肤神经内分泌癌，是一种高度侵袭性的 癌症的两年死亡率为40%。虽然MCC的发病率比黑色素瘤低25倍，但它 导致死亡的可能性要高出13倍。在非常短的时间内，MCC已经从一种未知的癌症发展到 检查点封锁疗法(CBT)成功的典范。随着强大的新技术的应用 工具给MCC的研究，可以预期，未来7年将继续带来令人瞩目的新 有可能增加我们对这种癌症以及许多其他癌症的洞察力的发现 井。有两种形式的MCC，病因不同，但表现几乎相同。病毒阴性 (VN)MCC是由于过度暴露在阳光下导致紫外线(UV)对 基因组，这是其他皮肤癌的典型模式，包括黑色素瘤、鳞状细胞癌和基底细胞癌 癌症。相反，病毒阳性(VP)MCC是由MCPyV病毒DNA整合到宿主中引起的 表达截短形式的大T抗原(LT)和完整的小T抗原(ST)的细胞基因组。 尽管VN-MCC和Vp-MCC的表型几乎相同，但它们在总体上有显著的差异 基因组突变率。VN-MCC的肿瘤突变负荷要高得多(TMB，中位数~40 突变/MB)高于VP-MCC(中位数2/MB)。VN-MCC具有几乎普遍的RB1和TP53失活 肿瘤抑制基因以及赖氨酸甲基转移酶基因KMT2C和KMT2D(也称为 ML3和MLL4)。此外，VN-MCC经常含有MYCL或MYC的扩增。相比之下，副总统- MCC可以通过存在整合的MCPyV基因组、没有紫外线突变来识别 特征，低TMB，以及很少的突变。相反，VP-MCC在功能上表达了MCPyV LT 灭活RB而ST招募MYCL到EP400染色质修饰复合体引发深刻变化 在基因表达上。 VP-MCC和VN-MCC之间的这些区别提出了一个问题，即我们可以对各自了解什么 一种MCC的形式，可以告诉我们关于另一个的情况。我们认为，肿瘤发生的不同机制 VN-MCC和VP-MCC为我们提供了使用正交方法获得 对MCC有更清晰的了解。我们认为MCPyV LT和ST的表达能够诱导相关的 在VP-MCC中观察到的通过RB1、TP53和TP53的失活突变发生的表型变化 VN-MCC中KMT2C/D基因和MYCL基因的扩增我们的癌症项目取得了显著进展 在区分VN-MCC和VP-MCC方面，现在准备利用这一机会利用 从每种类型的MCC中获得的见解将为另一种类型的MCC提供信息，这将导致对这种疾病的重大洞察。 此外，我们希望这些洞察力将为致癌途径提供有用的见解， 会导致其他类型的癌症。

Project Summary Merkel cell carcinoma (MCC) is a primary neuroendocrine carcinoma of the skin; a highly aggressive cancer with a 40% 2-year mortality rate. While the incidence of MCC is 25-fold less frequent than melanoma, it is 13-fold more likely to cause death. In a remarkably short time, MCC has gone from an unknown cancer to the poster child for the success of checkpoint blockade therapy (CBT). With the application of powerful new tools to the study of MCC, it can be expected that the next 7 years will continue to bring remarkable new discoveries with the potential to increase our insight not only into this cancer but into many other cancers as well. There are two forms of MCC with different etiologies but nearly identical presentations. Virus-negative (VN) MCC is caused by excessive sunlight exposure resulting in ultraviolet (UV) induced damage to the genome, a pattern typical for other skin cancers including melanoma, squamous cell carcinoma and basal cell carcinoma. In contrast, virus-positive (VP) MCC is caused by integration of the MCPyV viral DNA into the host cell genome with expression of a truncated form of Large T antigen (LT) and an intact Small T antigen (ST). Despite the near identical phenotypes, VN-MCC and VP-MCC have striking differences in their overall genome mutation rate. The VN-MCC has a much higher tumor mutational burden (TMB, median ~ 40 mutations/mB) than VP-MCC (median 2/mB). VN-MCC has near universal inactivation of the RB1 and TP53 tumor suppressor genes as well as in the lysine methyl transferase genes KMT2C and KMT2D (also known as MLL3 and MLL4). In addition, VN-MCC frequently contains amplification of MYCL or MYC. In contrast, VP- MCC can be recognized by the presence of integrated MCPyV genomes, the absence of UV mutation signature, a low TMB, and few if any mutations. Instead, VP-MCC expresses MCPyV LT that functionally inactivates RB while ST recruits MYCL to the EP400 chromatin modifying complex to induce profound changes in gene expressions. These distinctions between VP-MCC and VN-MCC raises the question of what we can learn about each form of MCC that can inform us about the other. We propose that the distinct mechanisms of oncogenesis in VN-MCC and VP-MCC provides us with the unique opportunity to use orthogonal methodologies to gain a clearer insight into MCC. We propose that expression of MCPyV LT and ST is capable of inducing the relevant phenotypic changes observed in VP-MCC that occur through the inactivating mutations of RB1, TP53, and KMT2C/D genes and amplification of MYCL in VN-MCC. Our cancer program has made remarkable progress in distinguishing between VN-MCC and VP-MCC and is now poised to exploit this opportunity to leverage insights gained from each type of MCC to inform the other that will lead to significant insights into this disease. Furthermore, we expect that these insights will provide useful insights into the oncogenic pathways that contribute to other cancer types.