Mitochondrial fusion drives oxidative metabolism to immortalize neural stem cells during tumorigenesis

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

代谢重编程是多种癌症的关键特征，但其如何以及何时参与肿瘤发生的机制仍未阐明。本研究证实，线粒体融合（mitochondrial fusion）诱导的代谢重编程可成为肿瘤起始细胞（tumor initiating cells, TICs）永生化的限速步骤，并触发其不可逆地定向于肿瘤发生程序。借助单细胞转录组学（single-cell transcriptomics）分析，我们发现果蝇脑肿瘤中存在一类快速增殖的干细胞群体，其核心特征为氧化磷酸化（oxidative phosphorylation, OxPhos）通路的上调表达。我们结合靶向代谢组学（targeted metabolomics）与体内遗传筛选（in-vivo genetic screening）实验证实，氧化磷酸化对于肿瘤细胞永生化是必需的，但在产生该肿瘤的神经干细胞（neural stem cells, NSCs）中并非必需。通过体内NADH/NAD+传感器（in-vivo NADH/NAD+ sensor），我们证明神经干细胞恰好在永生化过程中上调了氧化磷酸化水平。阻断氧化磷酸化或线粒体融合会使肿瘤起始细胞停滞于静息状态，并通过损害NAD+再生从而抑制肿瘤发生。本研究确立了细胞代谢与肿瘤起始细胞永生化之间的独特关联。