Oxidative Metabolism Drives Immortalization of Neural Stem Cells during Tumorigenesis

Cell. 2020 Sep 17;182(6):1490-1507.e19. doi: 10.1016/j.cell.2020.07.039. Epub 2020 Sep 10.


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 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. Blocking OxPhos or mitochondrial fusion stalls TICs in quiescence and prevents tumorigenesis through impaired NAD+ regeneration. Our work establishes a unique connection between cellular metabolism and immortalization of tumor-initiating cells.

Keywords: bioenergetics; cell immortalization; mitochondrial dynamics; neural stem cells; tumor heterogeneity; tumorigenesis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / metabolism*
  • Brain Neoplasms / mortality
  • Brain Neoplasms / pathology
  • Carcinogenesis / genetics
  • Carcinogenesis / metabolism*
  • Carcinogenesis / pathology
  • Cell Transformation, Neoplastic / metabolism*
  • Cell Transformation, Neoplastic / pathology
  • Citric Acid Cycle / genetics
  • Computational Biology
  • DNA-Binding Proteins / genetics
  • DNA-Binding Proteins / metabolism
  • Drosophila
  • Drosophila Proteins / genetics
  • Drosophila Proteins / metabolism
  • Glycolysis / genetics
  • Mass Spectrometry
  • Metabolomics
  • Microscopy, Electron, Transmission
  • Mitochondrial Dynamics*
  • Multigene Family
  • NAD / metabolism*
  • Neoplastic Stem Cells / metabolism*
  • Neural Stem Cells / metabolism*
  • Neural Stem Cells / pathology
  • Oxidative Phosphorylation*
  • Oxygen Consumption / genetics
  • RNA Interference
  • Reactive Oxygen Species / metabolism
  • Single-Cell Analysis
  • Transcriptome / genetics


  • DNA-Binding Proteins
  • Drosophila Proteins
  • Reactive Oxygen Species
  • brat protein, Drosophila
  • NAD