Methionine and PI3K Metabolism Drive CIMP in EBV Epithelial Cancers

蛋氨酸和 PI3K 代谢驱动 EBV 上皮癌中的 CIMP

基本信息

批准号：
10627692
负责人：
Benjamin Elison Gewurz
金额：
$ 47.11万
依托单位：
WISTAR INSTITUTE
依托单位国家：
美国
项目类别：
财政年份：
2023
资助国家：
美国
起止时间：
2023-05-11 至 2028-04-30
项目状态：
未结题

来源：
https://reporter.nih.gov/project-details/10627692
关键词：
Automobile Driving B-Lymphocytes BRCA1 gene Bacterial Artificial Chromosomes Bioinformatics Biological Assay Burkitt Lymphoma CRISPR screen Carbon Carcinoma Cell Death Cells Characteristics Chemicals Clustered Regularly Interspaced Short Palindromic Repeats Collaborations Communication CpG Island Methylator Phenotype DNA DNA Damage DNA Methylation DNA Repair Data Decitabine Disease Dose Enzymes Epigenetic Process Epithelial Cells Epithelium Epstein-Barr Virus Infections Epstein-Barr Virus latency Epstein-Barr Virus-Related Malignant Neoplasm Foundations G9a histone methyltransferase Genetic Genomics Glutathione Metabolism Pathway Growth Human Human Genome Human Herpesvirus 4 Hyperactivity Hypermethylation Integration Host Factors Isotopes Knock-out Knowledge Latent virus infection phase Learning Malignant Epithelial Cell Malignant Neoplasms Membrane Proteins Metabolic Metabolic Control Metabolic Pathway Metabolism Methionine Methionine Metabolism Pathway Methylation Modeling Mutagenesis Mutation Nasopharynx Carcinoma Oncogenic Organoids Oxidation-Reduction Oxidative Stress Pathway interactions Phosphatidylinositols Phosphotransferases Play Property Proteins Proto-Oncogene Proteins c-akt Reaction Recombinants Regulation Role S-Adenosylhomocysteine S-Adenosylmethionine Signal Transduction Somatic Mutation Stomach Carcinoma Testing The Cancer Genome Atlas Therapeutic Tropism Tumor Suppressor Proteins Viral Viral Genome Virus Latency Xenograft Model Xenograft procedure alpelisib antagonist cancer cell cancer genome dietary driver mutation epigenome gain of function gastric organoids genome-wide glutathione peroxidase histone methylation homologous recombination insight malignant stomach neoplasm metabolomics mouse model neoplastic cell novel novel therapeutic intervention personalized approach programs recombinational repair response transcription factor transcriptome sequencing tumor tumor metabolism ubiquitin-protein ligase

项目摘要

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.

项目3 - 项目摘要爱泼斯坦 - 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细胞的向流，但在200,000个与EBV相关的癌症中有一半以上每年发生的是胃癌和鼻咽癌。确定的癌症基因组图集项目 EBV感染的胃癌是四种生物学上不同的亚型之一。极端肿瘤基因组CPG岛甲基表型（CIMP）和功能获得的PI3K突变是显着特征，表明 EBV+ GC中互连的驾驶员角色。实际上，EBV+胃癌具有最高的DNA甲基化水平任何人类癌症。甲基化和PI3K活性升高也是EBV+ NPC的特征伯基特淋巴瘤，进一步表明这些致癌特性与高度的致病关系 EBV潜伏期的受限形式。然而，关于潜在的EBV突变如何与肿瘤驱动突变会导致上皮癌，以及如何通过精确方法将它们靶向。我们因此，使用EBV+上皮肿瘤细胞RNASEQ和CRISPR/CAS9筛选来识别其宿主因素敲除是合成致命的，降压剂去班滨或在阻塞时逆转了CIMP 高度选择性拮抗剂alpelisib的PI3K多动症。我们的中心假设是EBV+上皮癌症依靠潜在病毒基因组和多动PI3K和CIMP之间的串扰可以以合成致命方法为目标。我们的目的是（1）定义潜在EBV的作用驾驶cimp; （2）定义过度活跃PI3K信号在EBV+上皮癌中的作用，以支持CIMP；（3）在EBV+上皮癌中定义关键的合成致命脆弱性。总的来说，这些预计研究将确定如何颠覆EBV感染的上皮癌支持CIMP的代谢途径，以及CIMP不仅使肿瘤补充剂沉默，还如何沉默在防止DNA损伤的情况下发挥关键作用。因此，我们的研究可能支持发展的策略与EBV相关上皮癌的合理治疗方法。