PMID- 32916131
OWN - NLM
STAT- MEDLINE
DCOM- 20210519
LR  - 20210519
IS  - 1097-4172 (Electronic)
IS  - 0092-8674 (Linking)
VI  - 182
IP  - 6
DP  - 2020 Sep 17
TI  - Oxidative Metabolism Drives Immortalization of Neural Stem Cells during 
      Tumorigenesis.
PG  - 1490-1507.e19
LID - S0092-8674(20)30947-8 [pii]
LID - 10.1016/j.cell.2020.07.039 [doi]
AB  - 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.
CI  - Copyright (c) 2020 Elsevier Inc. All rights reserved.
FAU - Bonnay, Francois
AU  - Bonnay F
AD  - Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 
      1030 Vienna, Austria.
FAU - Veloso, Ana
AU  - Veloso A
AD  - Systems Biology of Neurogenesis, Berlin Institute for Medical Systems Biology 
      (BIMSB), Max Delbruck Center for Molecular Medicine in the Helmholtz Association 
      (MDC), 13125 Berlin, Germany.
FAU - Steinmann, Victoria
AU  - Steinmann V
AD  - Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 
      1030 Vienna, Austria.
FAU - Kocher, Thomas
AU  - Kocher T
AD  - Vienna Biocenter Core Facilities (VBCF), 1030 Vienna, Austria.
FAU - Abdusselamoglu, Merve Deniz
AU  - Abdusselamoglu MD
AD  - Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 
      1030 Vienna, Austria.
FAU - Bajaj, Sunanjay
AU  - Bajaj S
AD  - Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 
      1030 Vienna, Austria.
FAU - Rivelles, Elisa
AU  - Rivelles E
AD  - Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, 
      Austria.
FAU - Landskron, Lisa
AU  - Landskron L
AD  - Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 
      1030 Vienna, Austria.
FAU - Esterbauer, Harald
AU  - Esterbauer H
AD  - Department of Laboratory Medicine, Medical University of Vienna, 1090 Vienna, 
      Austria.
FAU - Zinzen, Robert P
AU  - Zinzen RP
AD  - Systems Biology of Neurogenesis, Berlin Institute for Medical Systems Biology 
      (BIMSB), Max Delbruck Center for Molecular Medicine in the Helmholtz Association 
      (MDC), 13125 Berlin, Germany.
FAU - Knoblich, Juergen A
AU  - Knoblich JA
AD  - Institute of Molecular Biotechnology of the Austrian Academy of Sciences (IMBA), 
      1030 Vienna, Austria. Electronic address: juergen.knoblich@imba.oeaw.ac.at.
LA  - eng
PT  - Journal Article
PT  - Research Support, Non-U.S. Gov't
DEP - 20200910
PL  - United States
TA  - Cell
JT  - Cell
JID - 0413066
RN  - 0 (DNA-Binding Proteins)
RN  - 0 (Drosophila Proteins)
RN  - 0 (Reactive Oxygen Species)
RN  - 0 (brat protein, Drosophila)
RN  - 0U46U6E8UK (NAD)
SB  - IM
CIN - Cell. 2020 Sep 17;182(6):1377-1378. PMID: 32946778
CIN - Nat Rev Mol Cell Biol. 2020 Nov;21(11):658-659. PMID: 32978604
CIN - EMBO J. 2020 Dec 1;39(23):e106927. PMID: 33128782
MH  - Animals
MH  - Brain Neoplasms/genetics/*metabolism/mortality/pathology
MH  - Carcinogenesis/genetics/*metabolism/pathology
MH  - Cell Transformation, Neoplastic/*metabolism/pathology
MH  - Citric Acid Cycle/genetics
MH  - Computational Biology
MH  - DNA-Binding Proteins/genetics/metabolism
MH  - Drosophila
MH  - Drosophila Proteins/genetics/metabolism
MH  - Glycolysis/genetics
MH  - Mass Spectrometry
MH  - Metabolomics
MH  - Microscopy, Electron, Transmission
MH  - *Mitochondrial Dynamics
MH  - Multigene Family
MH  - NAD/*metabolism
MH  - Neoplastic Stem Cells/*metabolism
MH  - Neural Stem Cells/*metabolism/pathology
MH  - *Oxidative Phosphorylation
MH  - Oxygen Consumption/genetics
MH  - RNA Interference
MH  - Reactive Oxygen Species/metabolism
MH  - Single-Cell Analysis
MH  - Transcriptome/genetics
OTO - NOTNLM
OT  - bioenergetics
OT  - cell immortalization
OT  - mitochondrial dynamics
OT  - neural stem cells
OT  - tumor heterogeneity
OT  - tumorigenesis
COIS- Declaration of Interests The authors declare no competing interests.
EDAT- 2020/09/12 06:00
MHDA- 2021/05/20 06:00
CRDT- 2020/09/11 20:11
PHST- 2020/06/17 00:00 [received]
PHST- 2020/06/24 00:00 [revised]
PHST- 2020/07/28 00:00 [accepted]
PHST- 2020/09/12 06:00 [pubmed]
PHST- 2021/05/20 06:00 [medline]
PHST- 2020/09/11 20:11 [entrez]
AID - S0092-8674(20)30947-8 [pii]
AID - 10.1016/j.cell.2020.07.039 [doi]
PST - ppublish
SO  - Cell. 2020 Sep 17;182(6):1490-1507.e19. doi: 10.1016/j.cell.2020.07.039. Epub 
      2020 Sep 10.