奥地利科学院（IMBA）分子生物技术研究所Juergen A. Knoblich研究组，揭示了氧化代谢驱动肿瘤发生过程中神经干细胞永生化。这一研究成果于2020年9月10日发表在《细胞》杂志上。

他们证明了由线粒体融合诱导的代谢重编程可以限制肿瘤诱发细胞（TICs）的永生化，并触发其不可逆的致癌作用。使用单细胞转录组学，他们发现果蝇脑肿瘤包含一个快速分裂的干细胞群体，该群体特征是氧化磷酸化（OxPhos）的上调。他们结合了靶向代谢组学和体内遗传筛选，以证明OxPhos是永生化肿瘤细胞所必需的，但在神经干细胞（NSCs）中却是不可缺少的，从而引起肿瘤。

利用体内NADH / NAD +传感器，他们显示NSC在永生化过程中OxPhos的确增加了。阻断OxPhos或线粒体融合会使TIC停滞，并通过受损的NAD +再生阻止肿瘤发生。他们的工作在细胞代谢与肿瘤起始细胞永生化之间建立了独特的联系。

据悉，代谢重编程是许多癌症的关键特征，但尚不清楚其如何以及何时促进肿瘤发生。

附：英文原文

Title: Oxidative Metabolism Drives Immortalization of Neural Stem Cells during Tumorigenesis

Author: Franois Bonnay, Ana Veloso, Victoria Steinmann, Thomas Kcher, Merve Deniz Abdusselamoglu, Sunanjay Bajaj, Elisa Rivelles, Lisa Landskron, Harald Esterbauer, Robert P. Zinzen, Juergen A. Knoblich

Issue&Volume: 2020-09-10

Abstract: Metabolic reprogramming is a key feature of many cancers, but how and when it contributesto tumorigenesis remains unclear. Here we demonstrate that metabolic reprogramminginduced by mitochondrial fusion can be rate-limiting for immortalization of tumor-initiatingcells (TICs) and trigger their irreversible dedication to tumorigenesis. Using single-celltranscriptomics, we find that Drosophila brain tumors contain a rapidly dividing stem cell population defined by upregulationof oxidative phosphorylation (OxPhos). We combine targeted metabolomics and in vivo genetic screening to demonstrate that OxPhos is required for tumor cell immortalizationbut dispensable in neural stem cells (NSCs) giving rise to tumors. Employing an in vivo NADH/NAD+ sensor, we show that NSCs precisely increase OxPhos during immortalization. BlockingOxPhos or mitochondrial fusion stalls TICs in quiescence and prevents tumorigenesisthrough impaired NAD+ regeneration. Our work establishes a unique connection between cellular metabolismand immortalization of tumor-initiating cells.

DOI: 10.1016/j.cell.2020.07.039

Source: https://www.cell.com/cell/fulltext/S0092-8674(20)30947-8