DNA damage repair kinase DNA‐PK and cGAS synergize to induce cancer‐related inflammation in glioblastoma - Archive ouverte HAL Accéder directement au contenu
Article Dans Une Revue EMBO Journal Année : 2023

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

Clara Taffoni
Soumyabrata Guha
Jean-Philippe Hugnot
Laura Fontenille
  • Fonction : Auteur

Résumé

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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Dates et versions

hal-03923380 , version 1 (13-10-2023)

Identifiants

Citer

Clara Taffoni, Johanna Marines, Hanane Chamma, Soumyabrata Guha, Mathilde Saccas, et al.. DNA damage repair kinase DNA‐PK and cGAS synergize to induce cancer‐related inflammation in glioblastoma. EMBO Journal, 2023, 42 (7), pp.e111961. ⟨10.15252/embj.2022111961⟩. ⟨hal-03923380⟩
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