Identification of Novel Oncogenic Signaling Pathways using Viral Perturbations

利用病毒扰动鉴定新型致癌信号通路

• 批准号: 10222618
• 负责人: James A. DeCaprio
• 金额: $ 103.52万
• 依托单位: DANA-FARBER CANCER INST
• 依托单位国家: 美国
• 财政年份: 2019
• 资助国家: 美国
• 起止时间: 2019-08-08 至 2026-07-31
• 项目状态: 未结题
• 来源: https://reporter.nih.gov/project-details/10222618
• 关键词: Basal cell carcinoma; Cause of Death; Cells; Child; Chromatin; Complex; Disease; Etiology; Gene Amplification; Gene Expression; Genome; Incidence; Large T Antigen; Learning; Lysine; MYCL1 gene; Malignant Epithelial Cell; Malignant Neoplasms; Merkel cell carcinoma; Methodology; Mutation; Oncogenic; Pathway interactions; Pattern; Phenotype; RB1 gene; Signal Pathway; Skin Cancer; Small T Antigen; Squamous cell carcinoma; Sun Exposure; TP53 gene; Time; Transferase; Tumor Suppressor Genes; UV induced; Viral; Virus; cancer type; immune checkpoint blockade; insight; melanoma; mortality; novel; posters; programs; recruit; success; tool; tumor; tumorigenesis; ultraviolet; viral DNA

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.

项目摘要 默克尔细胞癌（MCC）是皮肤的原发性神经内分泌癌;是一种高度侵袭性的恶性肿瘤。 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已经从一个未知的癌症， 检查点阻断疗法（CBT）成功的典范。随着强大的新技术的应用， 工具的MCC的研究，可以预计，未来7年将继续带来显着的新的 这些发现不仅有可能增加我们对这种癌症的了解，而且有可能增加我们对许多其他癌症的了解， 好. MCC有两种形式，病因不同，但表现几乎相同。病毒阴性 (VN)MCC是由过度的阳光照射导致的紫外线（UV）诱导的对皮肤的损伤引起的。 其他皮肤癌包括黑色素瘤、鳞状细胞癌和基底细胞癌， carcinoma.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。 尽管表型几乎相同，但VN-MCC和VP-MCC在其总体上具有显著差异。 基因组突变率VN-MCC具有高得多的肿瘤突变负荷（TMB，中值~ 40 突变/mB）比VP-MCC（中值2/mB）高。VN-MCC对RB 1和TP 53具有几乎普遍的失活作用 肿瘤抑制基因以及赖氨酸甲基转移酶基因KMT 2C和KMT 2D（也称为 MLL 3和MLL 4）。此外，VN-MCC经常含有MYCL或MYC的扩增。相反，VP- MCC可通过存在整合的MCPyV基因组、不存在UV突变、不存在DNA突变来识别。 标签，低TMB，以及很少的突变。相反，VP-MCC表达MCPyV LT， 使RB失活，而ST将MYCL募集至EP 400染色质修饰复合物以诱导深刻的变化 in gene基因expressions表达. VP-MCC和VN-MCC之间的这些区别提出了一个问题，即我们可以从每种情况中了解到什么 MCC的形式，可以告诉我们关于其他。我们认为，不同的肿瘤发生机制， VN-MCC和VP-MCC为我们提供了独特的机会，可以使用正交方法来获得 更清晰地了解MCC。我们认为，MCPyV LT和ST的表达能够诱导相关的细胞凋亡。 在VP-MCC中观察到的表型变化是通过RB 1、TP 53和 KMT 2C/D基因和VN-MCC中MYCL的扩增。我们的癌症项目已经取得了显著的进展 区分VN-MCC和VP-MCC，现在准备利用这一机会， 从每种类型的MCC获得的见解，以告知其他将导致对这种疾病的重要见解。 此外，我们期望这些见解将为致癌途径提供有用的见解， 导致其他癌症类型。