Activation of STING in the pancreatic tumor microenvironment: A novel therapeutic opportunity

Chamma, Hanane; Vila, Isabelle K.; Taffoni, Clara; Turtoï, Andrei; Laguette, Nadine

doi:10.1016/j.canlet.2022.215694

Cited by 19 publications

(18 citation statements)

References 90 publications

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“…The components of TME are complex, in which immune regulation and immune escape are important components. More and more studies have shown that TME plays a key role in tumor progression ( Wang et al, 2020b ; Chamma et al, 2022 ; Malla et al, 2022 ). In this study, we found that the overexpression of NPM1 was negatively correlated with most immune infiltrating cells in COAD and ESCA, but positively correlated with immune infiltrating cells in LIHC and PAAD.…”

Section: Discussionmentioning

confidence: 99%

“…Many studies have shown that the tumor microenvironment (TME) with extensive immune infiltration and N6-methyladenosine (m6A) modification that regulates gene stability play an important role in the occurrence and development of tumors and the diagnosis and treatment of cancer ( Chen et al, 2019 ; Wang et al, 2020a ; Chamma et al, 2022 ). At the same time, a recently discovered copper dependent regulatory cell death (cuproptosis) has become a research hotspot ( Cobine and Brady, 2022 ; Tang et al, 2022 ; Tsvetkov et al, 2022 ).…”

Section: Introductionmentioning

confidence: 99%

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Nucleophosmin 1 is a prognostic marker of gastrointestinal cancer and is associated with m6A and cuproptosis

Liu

Liu²,

Zeng³

et al. 2022

Front. Pharmacol.

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Background: NPM1 is highly expressed in a variety of solid tumors and promotes tumor development. However, there are few comprehensive studies on NPM1 analysis in gastrointestinal cancer.Methods: We used bioinformatics tools to study the expression difference of NPM1 between gastrointestinal cancer and control group, and analyzed the relationship between its expression level and the diagnosis, prognosis, functional signaling pathway, immune infiltration, m6A and cuproptosis related genes of gastrointestinal cancer. At the same time, the expression difference of NPM1 between esophageal carcinoma (ESCA) samples and control samples was verified by in vitro experiments.Results: NPM1 was overexpressed in gastrointestinal cancer. In vitro experiments confirmed that the expression of NPM1 in ESCA samples was higher than that in normal samples. The expression of NPM1 has high accuracy in predicting the outcome of gastrointestinal cancer. The expression of NPM1 is closely related to the prognosis of multiple gastrointestinal cancers. Go and KEGG enrichment analysis showed that NPM1 co-expressed genes involved in a variety of biological functions. NPM1 expression is potentially associated with a variety of immune cell infiltration, m6A and cuproptosis related genes in gastrointestinal cancers.Conclusion: NPM1 can be used as a diagnostic and prognostic marker of gastrointestinal cancer, which is related to the immune cell infiltration and the regulation of m6A and cuproptosis.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Nucleophosmin 1 is a prognostic marker of gastrointestinal cancer and is associated with m6A and cuproptosis

Liu

Liu²,

Zeng³

et al. 2022

Front. Pharmacol.

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“…[59,60] However, high expression of cGAS and/or STING has also been shown to predict poor outcome for cancer patients. [61] Tumour grade and origin, as well as the diversity of cells present in the tumour microenvironment and expression of immune checkpoints are parameters that likely contribute to dictate tumour immunogenicity, [62] supporting that further studies are required to avoid drawbacks of using STING agonists in clinics. [57]…”

Section: The Cgas-sting Pathway In Anti-tumoural Immunitymentioning

confidence: 99%

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

et al. 2023

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The cyclic GMP‐AMP synthase–stimulator of interferon genes (cGAS‐STING) pathway is central for the initiation of anti‐tumoural immune responses. Enormous effort has been made to optimise the design and administration of STING agonists to stimulate tumour immunogenicity. However, in certain contexts the cGAS‐STING axis fuels tumourigenesis. Here, we review recent findings on the regulation of cGAS expression and activity. We particularly focus our attention on the DNA‐dependent protein kinase (DNA‐PK) complex, that recently emerged as an activator of inflammatory responses in tumour cells. We propose that stratification analyses on cGAS and DNA‐PK expression/activation status should be carried out to predict treatment efficacy. We herein also provide insights into non‐canonical functions borne by cGAS and cGAMP, highlighting how they may influence tumourigenesis. All these parameters should be taken into consideration concertedly to choose strategies aiming to effectively boost tumour immunogenicity.

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“…In addition, the cGAS‐STING axis has been shown to support the survival of chromosomally unstable cancers (Hong et al , 2022 ), providing an explanation for cGAS‐STING inactivation in primary tumors (Bakhoum & Cantley, 2018 , Bakhoum et al , 2018 ) and activation in late tumorigenesis (Mayca Pozo et al , 2021 ). In addition to these tumor‐intrinsic parameters, the diversity of cells composing the tumor microenvironment and their differential expression of cGAS and/or STING are also determinant for tumor fate (Chamma et al , 2022a ). Prior studies have suggested that downregulation of the cGAS‐STING axis is an immune escape strategy exploited by tumor cells (Song et al , 2017 , Xia et al , 2016 ), despite evidence that high expression of cGAS and/or STING predicts poor outcome for cancer patients (An et al , 2019 ).…”

Section: Introductionmentioning

confidence: 99%

DNA damage repair kinase DNA‐PK and cGAS synergize to induce cancer‐related inflammation in glioblastoma

et al. 2022

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Cytosolic DNA promotes inflammatory responses upon detection by the cyclic GMP-AMP (cGAMP) synthase (cGAS). It has been suggested that cGAS downregulation is an immune escape strategy harnessed by tumor cells. Here, we used glioblastoma cells that show undetectable cGAS levels to address if alternative DNA detection pathways can promote pro-inflammatory signaling. We show that the DNA-PK DNA repair complex (i) drives cGAS-independent IRF3-mediated type I Interferon responses and (ii) that its catalytic activity is required for cGAS-dependent cGAMP production and optimal downstream signaling. We further show that the cooperation between DNA-PK and cGAS favors the expression of chemokines that promote macrophage recruitment in the tumor microenvironment in a glioblastoma model, a process that impairs early tumorigenesis but correlates with poor outcome in glioblastoma patients. Thus, our study supports that cGAS-dependent signaling is acquired during tumorigenesis and that cGAS and DNA-PK activities should be analyzed concertedly to predict the impact of strategies aiming to boost tumor immunogenicity.

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Activation of STING in the pancreatic tumor microenvironment: A novel therapeutic opportunity

Cited by 19 publications

References 90 publications

Nucleophosmin 1 is a prognostic marker of gastrointestinal cancer and is associated with m6A and cuproptosis

Nucleophosmin 1 is a prognostic marker of gastrointestinal cancer and is associated with m6A and cuproptosis

Harnessing the cooperation between DNA‐PK and cGAS in cancer therapies

DNA damage repair kinase DNA‐PK and cGAS synergize to induce cancer‐related inflammation in glioblastoma

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