TY  - JOUR
AU  - Geng, Haigang
AU  - Huang, Chen
AU  - Xu, Lei
AU  - Zhou, Yangyang
AU  - Dong, Zhongyi
AU  - Zhong, Yiqing
AU  - Li, Qian
AU  - Yang, Chen
AU  - Huang, Shaozhuo
AU  - Liao, Weixin
AU  - Lin, Yuxuan
AU  - Liu, Zhicheng
AU  - Li, Qing
AU  - Zhang, Zizhen
AU  - Zhu, Chunchao
TI  - Targeting cellular senescence as a therapeutic vulnerability in gastric cancer.
JO  - Life sciences
VL  - 346
SN  - 0024-3205
CY  - New York, NY [u.a.]
PB  - Elsevier Science
M1  - DKFZ-2024-00800
SP  - 122631
PY  - 2024
N1  - Volume 346, 1 June 2024, 122631
AB  - 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.
KW  - Cellular senescence (Other)
KW  - Drug repositioning (Other)
KW  - Exisulind (Other)
KW  - Gastric cancer (Other)
KW  - Immunosuppressive microenvironment (Other)
KW  - Multi-omics (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:38621585
DO  - DOI:10.1016/j.lfs.2024.122631
UR  - https://inrepo02.dkfz.de/record/289478
ER  -