衰老
癌症研究
癌症
帕博西利布
癌细胞
下调和上调
生物
医学
内科学
细胞生物学
生物化学
乳腺癌
基因
转移性乳腺癌
作者
Haigang Geng,Chen Huang,Xu Liu,Yangyang Zhou,Zhong‐Yi Dong,Yan Zhong,Qian Li,Chen Yang,Shaozhuo Huang,Weixin Liao,Yuxuan Lin,Zhicheng Liu,Qing Li,Zizhen Zhang,Chunchao Zhu
出处
期刊:Life Sciences
[Elsevier]
日期:2024-06-01
卷期号:346: 122631-122631
标识
DOI:10.1016/j.lfs.2024.122631
摘要
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.
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