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@ARTICLE{Geng:289478,
      author       = {H. Geng and C. Huang and L. Xu and Y. Zhou and Z. Dong and
                      Y. Zhong and Q. Li and C. Yang$^*$ and S. Huang and W. Liao
                      and Y. Lin and Z. Liu and Q. Li and Z. Zhang and C. Zhu},
      title        = {{T}argeting cellular senescence as a therapeutic
                      vulnerability in gastric cancer.},
      journal      = {Life sciences},
      volume       = {346},
      issn         = {0024-3205},
      address      = {New York, NY [u.a.]},
      publisher    = {Elsevier Science},
      reportid     = {DKFZ-2024-00800},
      pages        = {122631},
      year         = {2024},
      note         = {Volume 346, 1 June 2024, 122631},
      abstract     = {Cellular senescence (CS) represents an intracellular
                      defense mechanism responding to stress signals and can be
                      leveraged as a 'vulnerability' in cancer treatment. This
                      study aims to construct a CS atlas for gastric cancer (GC)
                      and uncover potential therapeutics for GC patients.38
                      senescence-associated regulators with prognostic
                      significance in GC were obtained from the CellAge database
                      to construct Gastric cancer-specific Senescence Score (GSS).
                      Using eXtreme Sum algorism, GSS-based drug repositioning was
                      conducted to identify drugs that could antagonize GSS in
                      CMap database. In vitro experiments were conducted to test
                      the effect of combination of palbociclib and exisulind in
                      eliminating GC cells.Patients with high GSS exhibited
                      CS-related features, such as CS markers upregulation,
                      adverse clinical outcomes and hypomethylation status.
                      scRNA-seq data showed malignant cells with high GSS
                      exhibited enhanced senescence state and more
                      immunosuppressive signals such as PVR-CD96 compared with
                      malignant cells with low GSS. In addition, the GSS-High
                      cancer associated fibroblasts might secrete cytokines and
                      chemokines such as IL-6, CXCL1, CXCL12, and CCL2 to from an
                      immunosuppressive microenvironment, and GSS could serve as
                      an indicator for immunotherapy resistance. Exisulind
                      exhibited the greatest potential to reverse GSS. In vitro
                      experiments demonstrated that exisulind could induce
                      apoptosis and suppress the proliferation of
                      palbociclib-induced senescent GC cells.Overall, GSS offers a
                      framework for better understanding of correlation between
                      senescence and GC, which might provide new insights into the
                      development of novel therapeutics in GC.},
      keywords     = {Cellular senescence (Other) / Drug repositioning (Other) /
                      Exisulind (Other) / Gastric cancer (Other) /
                      Immunosuppressive microenvironment (Other) / Multi-omics
                      (Other)},
      cin          = {D250},
      ddc          = {570},
      cid          = {I:(DE-He78)D250-20160331},
      pnm          = {314 - Immunologie und Krebs (POF4-314)},
      pid          = {G:(DE-HGF)POF4-314},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:38621585},
      doi          = {10.1016/j.lfs.2024.122631},
      url          = {https://inrepo02.dkfz.de/record/289478},
}