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@ARTICLE{Herter:304111,
      author       = {S. Herter$^*$ and M. Emperador$^*$ and K. Smyrilli$^*$ and
                      D. Kocher$^*$ and S. Celikyürekli$^*$ and C. Zeiser$^*$ and
                      X. Gerloff$^*$ and S. Kreth$^*$ and K.-O. Henrich$^*$ and K.
                      K. Maaß$^*$ and J. Rettenmeier$^*$ and T. Grünewald$^*$
                      and H. Peterziel$^*$ and F. Westermann$^*$ and A.
                      Hamacher-Brady and O. Witt$^*$ and I. Oehme$^*$},
      title        = {{H}igh content-imaging drug synergy screening identifies
                      specific senescence-related vulnerabilities of mesenchymal
                      neuroblastomas.},
      journal      = {Cell death $\&$ disease},
      volume       = {16},
      number       = {1},
      issn         = {2041-4889},
      address      = {London [u.a.]},
      publisher    = {Nature Publishing Group},
      reportid     = {DKFZ-2025-01774},
      pages        = {644},
      year         = {2025},
      note         = {#EA:B310#LA:B310#},
      abstract     = {Neuroblastomas encompass malignant cells with varying
                      degrees of differentiation, ranging from adrenergic (adr)
                      cells resembling the sympathoadrenal lineage to
                      undifferentiated, stem-cell-like mesenchymal (mes) cancer
                      cells. Relapsed neuroblastomas, which often have mesenchymal
                      features, have a poor prognosis and respond less to
                      anticancer therapies, necessitating the development of novel
                      treatment strategies. To identify novel treatment options,
                      we analyzed the sensitivity of 91 pediatric cell models,
                      including patient-derived tumoroid cultures, to a drug
                      library of 76 anti-cancer drugs at clinically relevant
                      concentrations. This included 24 three-dimensionally
                      cultured neuroblastoma cell lines representing the range of
                      mesenchymal to adrenergic subtypes. High-throughput
                      ATP-based luminescence measurements were compared to
                      high-content confocal imaging. With machine
                      learning-supported imaging analysis, we focused on changes
                      in the lysosomal compartment as a marker for therapy-induced
                      senescence and assessed the basal lysosomal levels in a
                      subset of untreated mesenchymal versus adrenergic cells. We
                      correlated these findings with pathway activity signatures
                      based on bulk RNA and scRNAseq. Comprehensive image-based
                      synergy screens with spheroid cultures validated the
                      combined effects of selected drugs on proliferation and
                      cytotoxicity. Mesenchymal models presented high basal
                      lysosomal levels correlating with senescence-associated
                      secretory phenotype (SASP) and sphingolipid metabolism
                      pathways. Chemotherapy treatment further increased lysosome
                      numbers, indicative of therapy-induced senescence.
                      Furthermore, the mesenchymal subtypes correlated with MAPK
                      activity and sensitivity to MAPK pathway inhibitors.
                      Lysosomal and SASP signaling is druggable by inhibitors of
                      lysosomal acid sphingomyelinase (SLMi) or senolytics,
                      including BCL2-family inhibitors. Especially the sequential
                      combination of MEK inhibitors (MEKi) with BCL2-family
                      inhibitors was the most effective on relapsed neuroblastoma
                      cell lines. Gene expression analysis of 223 patient samples,
                      drug sensitivity profiling of five patient-derived fresh
                      tissue cultures, and in vivo zebrafish embryo neuroblastoma
                      xenograft models confirmed these findings. Inhibition of
                      MAPK signaling in combination with BCL2-family inhibitors is
                      a novel treatment option for patients suffering from
                      relapsed neuroblastomas.},
      keywords     = {Humans / Neuroblastoma: pathology / Neuroblastoma: drug
                      therapy / Neuroblastoma: metabolism / Neuroblastoma:
                      genetics / Cellular Senescence: drug effects / Cell Line,
                      Tumor / Animals / Antineoplastic Agents: pharmacology / Drug
                      Synergism / Mesenchymal Stem Cells: drug effects /
                      Mesenchymal Stem Cells: metabolism / Mesenchymal Stem Cells:
                      pathology / Cell Proliferation: drug effects / Lysosomes:
                      metabolism / Lysosomes: drug effects / Zebrafish /
                      Antineoplastic Agents (NLM Chemicals)},
      cin          = {B310 / HD01 / B087 / B062 / B410},
      ddc          = {570},
      cid          = {I:(DE-He78)B310-20160331 / I:(DE-He78)HD01-20160331 /
                      I:(DE-He78)B087-20160331 / I:(DE-He78)B062-20160331 /
                      I:(DE-He78)B410-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:40854877},
      pmc          = {pmc:PMC12379013},
      doi          = {10.1038/s41419-025-07933-1},
      url          = {https://inrepo02.dkfz.de/record/304111},
}