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@ARTICLE{Koch:902967,
      author       = {Koch, Katharina and Hartmann, Rudolf and Suwala, Abigail
                      Kora and Rios, Dayana Herrera and Kamp, Marcel Alexander and
                      Sabel, Michael and Steiger, Hans-Jakob and Willbold, Dieter
                      and Sharma, Amit and Kahlert, Ulf Dietrich and Maciaczyk,
                      Jarek},
      title        = {{O}verexpression of {C}ystine/{G}lutamate {A}ntiporter
                      x{CT} {C}orrelates with {N}utrient {F}lexibility and {ZEB}1
                      {E}xpression in {H}ighly {C}lonogenic {G}lioblastoma
                      {S}tem-like {C}ells ({GSC}s)},
      journal      = {Cancers},
      volume       = {13},
      number       = {23},
      issn         = {2072-6694},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {FZJ-2021-04713},
      pages        = {6001 -},
      year         = {2021},
      abstract     = {Cancer stem-like cells mediate tumor initiation,
                      progression, and therapy resistance; however, their
                      identification and selective eradication remain challenging.
                      Herein, we analyze the metabolic dependencies of
                      glioblastoma stem-like cells (GSCs) with high-resolution
                      proton nuclear magnetic resonance (1H-NMR) spectroscopy. We
                      stratify our in vitro GSC models into two subtypes primarily
                      based on their relative amount of glutamine in relationship
                      to glutamate (Gln/Glu). Gln/GluHigh GSCs were found to be
                      resistant to glutamine deprivation, whereas Gln/GluLow GSCs
                      respond with significantly decreased in vitro clonogenicity
                      and impaired cell growth. The starvation resistance appeared
                      to be mediated by an increased expression of the
                      glutamate/cystine antiporter SLC7A11/xCT and efficient
                      cellular clearance of reactive oxygen species (ROS).
                      Moreover, we were able to directly correlate xCT-dependent
                      starvation resistance and high Gln/Glu ratios with in vitro
                      clonogenicity, since targeted differentiation of GSCs with
                      bone morphogenic protein 4 (BMP4) impaired xCT expression,
                      decreased the Gln/Glu ratio, and restored the sensitivity to
                      glutamine starvation. Moreover, significantly reduced levels
                      of the oncometabolites lactate (Lac), phosphocholine (PC),
                      total choline (tCho), myo-inositol (Myo-I), and glycine
                      (Gly) were observed in differentiated GSCs. Furthermore, we
                      found a strong association between high Gln/Glu ratios and
                      increased expression of Zinc finger E-box-binding homeobox 1
                      (ZEB1) and xCT in primary GBM tumor tissues. Our analyses
                      suggest that the inhibition of xCT represents a potential
                      therapeutic target in glioblastoma; thus, we could further
                      extend its importance in GSC biology and stress responses.
                      We also propose that monitoring of the intracellular Gln/Glu
                      ratio can be used to predict nutrient stress resistance.},
      cin          = {IBI-7},
      ddc          = {610},
      cid          = {I:(DE-Juel1)IBI-7-20200312},
      pnm          = {5244 - Information Processing in Neuronal Networks
                      (POF4-524)},
      pid          = {G:(DE-HGF)POF4-5244},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {34885110},
      UT           = {WOS:000762087200001},
      doi          = {10.3390/cancers13236001},
      url          = {https://juser.fz-juelich.de/record/902967},
}