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Oxidative Metabolism Drives Immortalization of Neural Stem Cells during Tumorigenesis.
Metadata
Journalcell38.637Date
2020 Sep 10
20 days ago
Type
Journal Article
Volume
2020-Sep-17 / 182 : 1490-1507.e19
Author
Bonnay F 1, Veloso A 2, Steinmann V 1, Köcher T 3, Abdusselamoglu MD 1, Bajaj S 1, Rivelles E 4, Landskron L 1, Esterbauer H 4, Zinzen RP 2, Knoblich JA 5
Affiliation
  • 2. Systems Biology of Neurogenesis, Berlin Institute for Medical Systems Biology (BIMSB), Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), 13125 Berlin, Germany.
  • 3. Vienna Biocenter Core Facilities (VBCF), 1030 Vienna, Austria.
  • 4. Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, Austria.
  • 5. Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 1030 Vienna, Austria. Electronic address: [email protected]
Doi
PMIDMESH
Abstract
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
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Cellcell
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LocationUnited States
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