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Oxidative metabolism drives immortalization of neural stem cells during tumorigenesis

Item Type:Article
Title:Oxidative metabolism drives immortalization of neural stem cells during tumorigenesis
Creators Name:Bonnay, F. and Veloso, A. and Steinmann, V. and Köcher, T. and Abdusselamoglu, M.D. and Bajaj, S. and Rivelles, E. and Landskron, L. and Esterbauer, H. and Zinzen, R.P. and Knoblich, J.A.
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:Tumorigenesis, Neural Stem Cells, Cell Immortalization, Bioenergetics, Mitochondrial Dynamics, Tumor Heterogeneity
Source:Cell
ISSN:0092-8674
Publisher:Cell Press
Volume:182
Number:6
Page Range:1490-1507
Date:17 September 2020
Official Publication:https://doi.org/10.1016/j.cell.2020.07.039
PubMed:View item in PubMed

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