2. Academic Validation
  3. Targeting cellular senescence as a therapeutic vulnerability in gastric cancer

Targeting cellular senescence as a therapeutic vulnerability in gastric cancer

  • Life Sci. 2024 Jun 1:346:122631. doi: 10.1016/j.lfs.2024.122631.
Haigang Geng 1,  Chen Huang 1,  Lei Xu 2,  Yangyang Zhou 3,  Zhongyi Dong 1,  Yiqing Zhong 1,  Qian Li 4,  Chen Yang 5,  Shaozhuo Huang 6,  Weixin Liao 7,  Yuxuan Lin 1,  Zhicheng Liu 2,  Qing Li 8,  Zizhen Zhang 9,  Chunchao Zhu 10
Affiliations

Affiliations

  • 1 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China.
  • 2 Hepatic Surgery Center, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, 430030 Wuhan, Hubei, China.
  • 3 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
  • 4 Department of Oncology, Shanghai Jiao Tong University Affiliated Sixth People's Hospital, Shanghai, China.
  • 5 State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China; Immune Regulation in Cancer Group, German Cancer Research Center (DKFZ), Heidelberg 69120, Germany.
  • 6 Department of Medical Oncology, Erasmus MC Cancer Institute, Erasmus University Medical Center, 3015 GD Rotterdam, the Netherlands.
  • 7 Department of Cell and Chemical Biology, Leiden University Medical Center, Leiden, Netherlands.
  • 8 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China; State Key Laboratory of Oncogenes and Related Genes, Shanghai Cancer Institute, Renji Hospital, Shanghai Jiao Tong University School of Medicine, China.
  • 9 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
  • 10 Department of Gastrointestinal Surgery, Renji Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China. Electronic address: [email protected].
PMID: 38621585 DOI: 10.1016/j.lfs.2024.122631
Abstract

Aims: 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.

Materials and methods: 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.

Key findings: 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.

Significance: 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; Drug repositioning; Exisulind; Gastric cancer; Immunosuppressive microenvironment; Multi-omics.

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