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@ARTICLE{Srchen:274486,
      author       = {V. Särchen and L. M. Reindl and S. Wiedemann and S.
                      Shanmugalingam and T. Bukur and J. Becker and M. Suchan and
                      E. Ullrich$^*$ and M. Vogler$^*$},
      title        = {{C}haracterization of {BV}6-{I}nduced {S}ensitization to
                      the {NK} {C}ell {K}illing of {P}ediatric {R}habdomyosarcoma
                      {S}pheroids.},
      journal      = {Cells},
      volume       = {12},
      number       = {6},
      issn         = {2073-4409},
      address      = {Basel},
      publisher    = {MDPI},
      reportid     = {DKFZ-2023-00629},
      pages        = {906},
      year         = {2023},
      abstract     = {Although the overall survival in pediatric rhabdomyosarcoma
                      (RMS) has increased over the last decades, the most
                      aggressive subtype of alveolar RMS is in dire need of novel
                      treatment strategies. RMS cells evade cell death induction
                      and immune control by increasing the expression of
                      inhibitors of apoptosis proteins (IAPs), which can be
                      exploited and targeted with stimulation with Smac mimetics.
                      Here, we used the Smac mimetic BV6 to re-sensitize RMS
                      spheroids to cell death, which increased killing induced by
                      natural killer (NK) cells. Single BV6 treatment of RMS
                      spheroids did not reduce spheroidal growth. However, we
                      observed significant spheroidal decomposition upon BV6
                      pre-treatment combined with NK cell co-cultivation.
                      Molecularly, IAPs s are rapidly degraded by BV6, which
                      activates NF-κB signal transduction pathways in RMS
                      spheroids. RNA sequencing analysis validated NF-κB
                      activation and identified a plethora of BV6-regulated genes.
                      Additionally, BV6 released caspases from IAP-mediated
                      inhibition. Here, caspase-8 might play a major role, as
                      knockdown experiments resulted in decreased NK cell-mediated
                      attack. Taken together, we improved the understanding of the
                      BV6 mechanism of RMS spheroid sensitization to cytotoxic
                      immune cells, which could be suitable for the development of
                      novel combinatory cellular immunotherapy with Smac
                      mimetics.},
      keywords     = {BV6 (Other) / NK cells (Other) / Smac mimetic (Other) /
                      cell death (Other) / rhabdomyosarcoma (Other) / tumor
                      spheroids (Other)},
      cin          = {FM01},
      ddc          = {570},
      cid          = {I:(DE-He78)FM01-20160331},
      pnm          = {899 - ohne Topic (POF4-899)},
      pid          = {G:(DE-HGF)POF4-899},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:36980247},
      doi          = {10.3390/cells12060906},
      url          = {https://inrepo02.dkfz.de/record/274486},
}