Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity

Zheng, Tiansheng; Su, Hang; Wang, Fei; Dang, Yifang; Ren, Yijiu; Yin, Shenyi; Lü, Honghua; Zhang, Hang; Wu, Jun; Xu, Zhu; Zheng, Mengge; Gao, Jiani; Cao, Yinhe; Xu, Junfang; Chen, Li; Wu, Xiangyang; Ma, Mingtong; Xu, Long; Wang, Fang; Chen, Jianxia; Su, Chunxia; Wu, Chunyan; Xie, Huikang; Gu, Jianhong; Xi, Jianzhong; Ge, Baoxue; Fei, Yiyan; Chen, Chang

doi:10.1016/j.celrep.2023.112275

Cited by 6 publications

(3 citation statements)

References 96 publications

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“…Brivanib is a dual-target inhibitor of vascular endothelial growth factor receptor and fibroblast growth factor receptor. Recent studies have revealed that Brivanib can inhibit angiogenesis and target cGAS to enhance the antitumor immune response [47]. Our findings indicated that this signature has the potential to aid the discovery and identify therapeutic drug targets for the treatment of gastric cancer, which need further studies.…”

Section: Discussionmentioning

confidence: 72%

Comprehensive Analysis of Disulfidptosis-Related LncRNAs in Molecular Classification, Immune Microenvironment Characterization and Prognosis of Gastric Cancer

Kang,

Li,

Peng

et al. 2023

Biomedicines

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Background: Disulfidptosis is a novel form of programmed cell death that unveils promising avenues for the exploration of tumor treatment modalities. Gastric cancer (GC) is a malignant tumor characterized by high incidence and mortality rate. However, there has been no systematic study of disulfidptosis-related long noncoding RNAs (DRLs) signature in GC patients. Methods: The lncRNA expression profiles containing 412 GC samples were acquired from the Cancer Genome Atlas (TCGA) database. Differential expression analysis was performed alongside Pearson correlation analysis to identify DRLs. Prognostically significant DRLs were further screened using univariate COX regression analysis. Subsequently, LASSO regression and multifactorial COX regression analyses were employed to establish a risk signature composed of DRLs that exhibit independent prognostic significance. The predictive value of this risk signature was further validated in a test cohort. The ESTIMATE, CIBERSORT and ssGSEA methodologies were utilized to investigate the tumor immune microenvironment of GC populations with different DRLs profiles. Finally, the correlation between DRLs and various GC drug responses was explored. Results: We established a prognostic signature comprising 12 disulfidptosis-related lncRNAs (AC110491.1, AL355574.1, RHPN1-AS1, AOAH-IT1, AP001065.3, MEF2C-AS1, AC016394.2, LINC00705, LINC01952, PART1, TNFRSF10A-AS1, LINC01537). The Kaplan–Meier survival analysis revealed that patients in the high-risk group exhibited a poor prognosis. Both univariate and multivariate COX regression models demonstrated that the DRLs signature was an independent prognostic indicator in GC patients. Furthermore, the signature exhibited accurate predictions of survival at 1-, 3- and 5- years with the area under the curve (AUC) values of 0.708, 0.689 and 0.854, respectively. In addition, we also observed significant associations between the DRLs signature and various clinical variables, distinct immune landscape and drug sensitivity profiles in GC patients. The low-risk group patients may be more likely to benefit from immunotherapy and chemotherapy. Conclusions: Our study investigated the role and potential clinical implications of DRLs in GC. The risk model constructed by DRLs demonstrated high accuracy in predicting the survival outcomes of GC and improving the treatment efficacy for GC patients.

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Section: Discussionmentioning

confidence: 72%

Comprehensive Analysis of Disulfidptosis-Related LncRNAs in Molecular Classification, Immune Microenvironment Characterization and Prognosis of Gastric Cancer

Kang,

Li,

Peng

et al. 2023

Biomedicines

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“…PTC tests of 59 patients with gastric, colorectal, or breast cancers revealed an overall accuracy of 93% in predicting their clinical outcomes. Additionally, Liu et al generated PTC models from lung cancer patients that structurally and functionally recapitulated the original tumor features and exhibited a high degree of morphological similarities to surgically resected samples, which can be used to assess the efficacy of cisplatin-based chemotherapy ( Liu et al, 2023a ). Zhang et al evaluated the responses of PTCs to specific drugs or combinations of drugs ( Zhang et al, 2023a ).…”

Section: Models For Tumor Researchmentioning

confidence: 99%

Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research

Yan,

He,

Zhu

et al. 2024

Front. Cell Dev. Biol.

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Gastrointestinal cancers account for approximately one-third of the total global cancer incidence and mortality with a poor prognosis. It is one of the leading causes of cancer-related deaths worldwide. Most of these diseases lack effective treatment, occurring as a result of inappropriate models to develop safe and potent therapies. As a novel preclinical model, tumor patient-derived organoids (PDOs), can be established from patients’ tumor tissue and cultured in the laboratory in 3D architectures. This 3D model can not only highly simulate and preserve key biological characteristics of the source tumor tissue in vitro but also reproduce the in vivo tumor microenvironment through co-culture. Our review provided an overview of the different in vitro models in current tumor research, the derivation of cells in PDO models, and the application of PDO model technology in gastrointestinal cancers, particularly the applications in combination with CRISPR/Cas9 gene editing technology, tumor microenvironment simulation, drug screening, drug development, and personalized medicine. It also elucidates the ethical status quo of organoid research and the current challenges encountered in clinical research, and offers a forward-looking assessment of the potential paths for clinical organoid research advancement.

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“…cGAS-STING pathway not only inhibits tumor progression, but also promotes tumor progression. On the one hand, cGAS-STING pathway plays an anti-tumor role in melanoma ( 65 ), small cell lung cancer ( 66 ), breast cancer ( 67 , 68 ) and colon cancer ( 69 ) by promoting the activation of immune cells, cell apoptosis and tumor vascular remodeling. On the other hand, cGAS-STING pathway promotes tumor progression in melanoma ( 70 ), breast cancer ( 71 , 72 ), lung cancer ( 73 ) and skin cancer ( 74 ) by promoting tumor immune escape and metastasis and maintaining chronic inflammation.…”

Section: Brief Introduction Of Cgas and Its Canonical Functionmentioning

confidence: 99%

cGAS: action in the nucleus

Lu,

Zhao,

Chen

et al. 2024

Front. Immunol.

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As a canonical cytoplasmic DNA sensor, cyclic GMP-AMP synthase (cGAS) plays a key role in innate immunity. In recent years, a growing number of studies have shown that cGAS can also be located in the nucleus and plays new functions such as regulating DNA damage repair, nuclear membrane repair, chromosome fusion, DNA replication, angiogenesis and other non-canonical functions. Meanwhile, the mechanisms underlying the nucleo-cytoplasmic transport and the regulation of cGAS activation have been revealed in recent years. Based on the current understanding of the structure, subcellular localization and canonical functions of cGAS, this review focuses on summarizing the mechanisms underlying nucleo-cytoplasmic transport, activity regulation and non-canonical functions of cGAS in the nucleus. We aim to provide insights into exploring the new functions of cGAS in the nucleus and advance its clinical translation.

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Pharmacological boosting of cGAS activation sensitizes chemotherapy by enhancing antitumor immunity

Cited by 6 publications

References 96 publications

Comprehensive Analysis of Disulfidptosis-Related LncRNAs in Molecular Classification, Immune Microenvironment Characterization and Prognosis of Gastric Cancer

Comprehensive Analysis of Disulfidptosis-Related LncRNAs in Molecular Classification, Immune Microenvironment Characterization and Prognosis of Gastric Cancer

Human patient derived organoids: an emerging precision medicine model for gastrointestinal cancer research

cGAS: action in the nucleus

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