UPMC Hillman Cancer Center, Department of Medicine, University of Pittsburgh Medical Center, Pittsburgh, PA, USA.
Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, NY 10032, USA.
Cell Metab. 2024 Nov 5;36(11):2419-2436.e8. doi: 10.1016/j.cmet.2024.09.014. Epub 2024 Oct 24.
Tumors reprogram their metabolism to generate complex neoplastic ecosystems. Here, we demonstrate that glioblastoma (GBM) stem cells (GSCs) display elevated activity of the malate-aspartate shuttle (MAS) and expression of malate dehydrogenase 2 (MDH2). Genetic and pharmacologic targeting of MDH2 attenuated GSC proliferation, self-renewal, and in vivo tumor growth, partially rescued by aspartate. Targeting MDH2 induced accumulation of alpha-ketoglutarate (αKG), a critical co-factor for dioxygenases, including the N6-methyladenosine (m6A) RNA demethylase AlkB homolog 5, RNA demethylase (ALKBH5). Forced expression of MDH2 increased m6A levels and inhibited ALKBH5 activity, both rescued by αKG supplementation. Reciprocally, targeting MDH2 reduced global m6A levels with platelet-derived growth factor receptor-β (PDGFRβ) as a regulated transcript. Pharmacological inhibition of MDH2 in GSCs augmented efficacy of dasatinib, an orally bioavailable multi-kinase inhibitor, including PDGFRβ. Collectively, stem-like tumor cells reprogram their metabolism to induce changes in their epitranscriptomes and reveal possible therapeutic paradigms.
肿瘤重新编程其代谢以产生复杂的肿瘤生态系统。在这里，我们证明神经胶质瘤（GBM）干细胞（GSCs）表现出苹果酸天冬氨酸穿梭（MAS）的活性升高和苹果酸脱氢酶 2（MDH2）的表达。MDH2 的遗传和药理学靶向降低了 GSC 的增殖、自我更新和体内肿瘤生长，天冬氨酸部分挽救了这一作用。靶向 MDH2 诱导α-酮戊二酸（αKG）的积累，αKG 是包括 N6-甲基腺苷（m6A）RNA 去甲基酶 AlkB 同源物 5 和 RNA 去甲基酶（ALKBH5）在内的双加氧酶的关键辅因子。强制表达 MDH2 增加了 m6A 水平并抑制了 ALKBH5 活性，这两者都可以通过 αKG 补充来挽救。相反，靶向 MDH2 降低了血小板衍生生长因子受体-β（PDGFRβ）作为受调控转录物的全局 m6A 水平。在 GSCs 中，MDH2 的药理学抑制增强了达沙替尼的疗效，达沙替尼是一种口服生物可利用的多激酶抑制剂，包括 PDGFRβ。总之，类干细胞肿瘤细胞重新编程其代谢以诱导其表观转录组发生变化，并揭示了可能的治疗范例。
