Methionine and PI3K Metabolism Drive CIMP in EBV Epithelial Cancers

项目3--项目总结 爱泼斯坦-巴尔病毒(EBV)与多种上皮细胞疾病有关，包括胃癌和 鼻咽癌。尽管有B细胞嗜性，但在20万与EBV相关的癌症中，超过一半的人 每年发生的是胃癌和鼻咽癌。癌症基因组图谱项目确定 EBV感染的胃癌是四种不同的生物学亚型之一。极端肿瘤基因组CpG岛 甲基化表型(CIMP)和功能获得性PI3K突变是显著特征，提示 EBV+GC中相互关联的驱动因素。事实上，EBV+胃癌的DNA甲基化水平最高 任何人类癌症的可能性。高甲基化和PI3K活性升高也是EBV+NPC和 Burkitt淋巴瘤，进一步表明这些致癌特性与高度 有限形式的EBV潜伏期。然而，关于潜在的EBV变异如何与 肿瘤驱动因素突变导致上皮性癌症，以及如何通过精确的方法将这些癌症作为靶点。我们 因此使用EBV+上皮性肿瘤细胞RNAseq和CRISPR/Cas9筛查来鉴定其宿主因子 基因敲除是一种合成致死物质，通过去甲基化药物地西他滨逆转CIMP，或在阻断 高选择性拮抗剂alpelisib对PI3K的激活作用。我们的中心假设是EBV+上皮细胞 癌症依赖于潜伏的病毒基因组之间的串扰，以及过度活跃的PI3K和CIMP，干扰 它可以成为合成致命方法的靶子。我们的目标是(1)定义潜伏的EBV在 (2)明确高活性PI3K信号在EBV+上皮性肿瘤中支持CIMP的作用； (3)确定EBV+上皮癌CIMP逆转的关键合成致死脆弱性。总而言之，这些 研究有望确定EBV感染的上皮性癌症如何颠覆宿主蛋氨酸和PI3K 支持CIMP的代谢途径，以及CIMP如何反过来不仅沉默肿瘤抑制因子，而且还 在防止DNA损伤方面起着关键作用。因此，我们的研究可能会支持制定战略 EB病毒相关上皮性癌症的合理治疗方法。

PROJECT 3 – PROJECT SUMMARY Epstein-Barr virus (EBV) is associated with multiple epithelial cell diseases, including gastric cancer and nasopharyngeal carcinoma. Despite its B-cell tropism, more than half of the 200,000 EBV-associated cancers that occur annually are gastric and nasopharyngeal carcinomas. The Cancer Genome Atlas project identified EBV-infected gastric cancer as one of the four biologically distinct subtypes. Extreme tumor genome CpG island methylator phenotype (CIMP) and gain-of-function PI3K mutations are salient features, suggesting interconnected driver roles in EBV+ GC. In fact, EBV+ gastric cancer has the highest level of DNA methylation of any human cancer. Hypermethylation and elevated PI3K activity are also characteristic of EBV+ NPC and Burkitt lymphoma, further suggesting a close pathogenetic relationship of these oncogenic properties with highly restricted forms of EBV latency. Yet, much remains to be learned about how latent EBV mutation together with tumor driver mutations result in epithelial cancers, and how these can be targeted by precision approaches. We therefore used EBV+ epithelial tumor cell RNAseq and CRISPR/Cas9 screens to identify host factors whose knockout is synthetic lethal with reversal of CIMP by the hypomethylating agent decitabine or upon blockade of PI3K hyperactivity by the highly selective antagonist alpelisib. Our central hypothesis is that EBV+ epithelial cancers rely on cross-talk between latent viral genomes, and hyperactive PI3K and CIMP, disruption of which can be targeted in synthetic lethal approaches. Our Aims are to (1) Define the role of latent EBV in driving CIMP; (2) Define the role of hyperactive PI3K signaling in EBV+ epithelial cancers in support of CIMP; (3) Define key synthetic lethal vulnerabilities upon EBV+ epithelial cancer CIMP reversal. Collectively, these studies are expected to identify how EBV-infected epithelial cancers subvert host methionine and PI3K metabolism pathways to support CIMP, and how in turn CIMP not only silences tumor suppressors, but also plays key roles in guarding against DNA damage. Our studies may therefore support strategies to develop rational therapeutic approaches for EBV-associated epithelial cancers.