Havey Larissa, You Haixi, Asara John M, Wang Yin, Guo Rui
Department of Molecular Biology and Microbiology, Tufts University, Boston, MA 02111.
Division of Signal Transduction, Beth Israel Deaconess Medical Center and Department of Medicine, Harvard Medical School, Boston, MA 02115.
Res Sq. 2025 Apr 24:rs.3.rs-6506954. doi: 10.21203/rs.3.rs-6506954/v1.
Epstein-Barr virus (EBV) contributes to over 200,000 cancers annually, predominantly aggressive lymphomas originating from hypoxic germinal centers (< 1% O). However, conventional models fail to recapitulate the physiologically relevant hypoxic microenvironment which profoundly influences B-cell metabolic remodeling during transformation. Here, we establish an model of EBV-driven B-cell transformation under 1% O, demonstrating robust transformation and super-enhancer activation of oncogenic regulators, including MYC. Multi-omic analyses reveal distinct metabolic adaptations to hypoxia. Unlike normoxic B-cells, which rely on fatty acid desaturases and oxidation to mitigate lipotoxicity, hypoxically transformed B-cells suppress fatty acid synthesis while upregulating glycerophospholipid metabolism and lipid droplet formation to buffer excess saturated lipids. Consequently, these cells exhibit heightened dependence on external unsaturated fatty acids to support proliferation. Our findings provide the first physiologically relevant model of EBV-driven B-cell transformation under hypoxia, uncovering metabolic vulnerabilities that could inform targeted therapeutic strategies for EBV-associated malignancies.
爱泼斯坦-巴尔病毒（EBV）每年导致超过20万例癌症，主要是起源于低氧生发中心（氧含量<1%）的侵袭性淋巴瘤。然而，传统模型无法重现生理相关的低氧微环境，而这种微环境在转化过程中对B细胞代谢重塑有深远影响。在此，我们建立了一个在1%氧含量条件下EBV驱动的B细胞转化模型，证明了致癌调节因子（包括MYC）的强大转化和超级增强子激活。多组学分析揭示了对低氧的独特代谢适应。与依赖脂肪酸去饱和酶和氧化来减轻脂毒性的常氧B细胞不同，低氧转化的B细胞抑制脂肪酸合成，同时上调甘油磷脂代谢和脂滴形成，以缓冲过量的饱和脂质。因此，这些细胞对外部不饱和脂肪酸的依赖性增强以支持增殖。我们的研究结果提供了首个生理相关的低氧条件下EBV驱动的B细胞转化模型，揭示了代谢弱点，可为EBV相关恶性肿瘤的靶向治疗策略提供依据。
