MTHFD1L相关的支链氨基酸降解转录特征代表EBV相关恶性肿瘤中一种保守的代谢程序

文献信息

中文摘要

背景： EBV相关恶性肿瘤涵盖多种组织来源不同的肿瘤类型，但它们共享保守代谢程序的程度仍知之甚少。方法：在此，我们对鼻咽癌、EBV相关胃癌和EBV相关浆母细胞淋巴瘤进行了整合的跨癌种转录组分析，以识别保守的代谢程序，随后进行了独立队列验证和单细胞转录组表征。结果：我们在三个发现队列中识别出103个共识差异表达基因和72个保守的基因-代谢通路对。其中，只有MTHFD1L相关的缬氨酸、亮氨酸和异亮氨酸降解程序在发现队列和验证队列中均持续保留。单细胞分析进一步表明，这一保守代谢程序主要富集于CD4+ T细胞、γδ T细胞和NK细胞，并伴随细胞状态依赖的代谢重塑、细胞间通讯改变以及不同免疫细胞群中以MTHFD1L为中心的独特调控网络。结论：总体而言，我们的研究确定了MTHFD1L相关的支链氨基酸降解转录共表达特征作为EBV相关恶性肿瘤共享的一种保守代谢程序，并揭示了其免疫细胞特异性和动态特征。这些发现为EBV相关恶性肿瘤的代谢适应提供了新见解，并为病毒相关癌症的代谢靶向治疗策略开发提供了概念框架。

英文摘要

Epstein-Barr virus (EBV)-associated malignancies encompass multiple tumor types with distinct tissue origins, yet the extent to which they share conserved metabolic programs remains poorly understood. Here, we performed an integrated cross-cancer transcriptomic analysis of nasopharyngeal carcinoma, EBV-associated gastric cancer, and EBV-associated plasmablastic lymphoma to identify conserved metabolic programs, followed by independent cohort validation and single-cell transcriptomic characterization. We identified 103 consensus differentially expressed genes and 72 conserved gene-metabolic pathway pairs across the three discovery cohorts. Among them, only the MTHFD1L-associated Valine, leucine and isoleucine degradation program was consistently preserved in both the discovery and validation cohorts. Single-cell analysis further demonstrated that this conserved metabolic program was predominantly enriched in CD4+ T cells, γδ T cells, and NK cells, and was accompanied by cell state-dependent metabolic remodeling, altered cell-cell communication, and distinct MTHFD1L-centered regulatory networks across immune cell populations. Collectively, our study identifies an MTHFD1L-associated branched-chain amino acid degradation transcriptional co-expression signature as a conserved metabolic program shared across EBV-associated malignancies and reveals its immune cell-specific and dynamic characteristics. These findings provide new insight into the metabolic adaptation of EBV-associated malignancies and offer a conceptual framework for the development of metabolism-targeted therapeutic strategies for virus-associated cancers.