DNA damage repair kinase DNA-PK and cGAS synergize to induce cancer-related inflammation in glioblastoma.
DNA damage repair kinase DNA-PK and cGAS synergize to induce cancer-related inflammation in glioblastoma.
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DOI：
10.15252/embj.2022111961
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发表时间：
2023-04-03
期刊：
影响因子：
--
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细胞溶质DNA在通过环GMP-AMP（cGAMP）合酶（cGAS）检测时促进炎症反应。已经表明cGAS下调是肿瘤细胞利用的免疫逃逸策略。在这里，我们使用了表现出不可检测的cGAS水平的胶质母细胞瘤细胞来解决替代DNA检测途径是否可以促进促炎信号传导。我们表明，DNA-PK DNA修复复合物（i）驱动cGAS非依赖性IRF 3介导的I型干扰素反应，（ii）其催化活性是cGAS依赖性cGAMP产生和最佳下游信号传导所必需的。我们进一步表明，DNA-PK和cGAS之间的合作有利于促进胶质母细胞瘤模型中肿瘤微环境中巨噬细胞募集的趋化因子的表达，这一过程损害了早期肿瘤发生，但与胶质母细胞瘤患者的不良结局相关。因此，我们的研究支持cGAS依赖性信号在肿瘤发生过程中获得，并且应该协调分析cGAS和DNA-PK活性，以预测旨在增强肿瘤免疫原性的策略的影响。DNA-PK与cGAS-STING信号传导合作，调节I型干扰素、趋化因子和肿瘤相关的炎症反应。
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. DNA‐PK cooperates with cGAS‐STING signalling to regulate type I Interferons, chemokines and tumor‐related inflammatory responses.
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DOI：
10.1093/brain/awx253
发表时间：
2017-11-01
期刊：
Brain : a journal of neurology
影响因子：
--
作者：
Harford-Wright E;Andre-Gregoire G;Jacobs KA;Treps L;Le Gonidec S;Leclair HM;Gonzalez-Diest S;Roux Q;Guillonneau F;Loussouarn D;Oliver L;Vallette FM;Foufelle F;Valet P;Davenport AP;Glen RC;Bidere N;Gavard J
通讯作者：
Gavard J
染色体不稳定性通过胞质DNA反应驱动转移。
影响因子：
64.8
作者：
Bakhoum SF;Ngo B;Laughney AM;Cavallo JA;Murphy CJ;Ly P;Shah P;Sriram RK;Watkins TBK;Taunk NK;Duran M;Pauli C;Shaw C;Chadalavada K;Rajasekhar VK;Genovese G;Venkatesan S;Birkbak NJ;McGranahan N;Lundquist M;LaPlant Q;Healey JH;Elemento O;Chung CH;Lee NY;Imielenski M;Nanjangud G;Pe'er D;Cleveland DW;Powell SN;Lammerding J;Swanton C;Cantley LC
通讯作者：
Cantley LC
影响因子：
11.4
作者：
Gonzalez-Suarez, Ignacio;Redwood, Abena B.;Gonzalo, Susana
通讯作者：
Gonzalo, Susana
DOI：
10.1073/pnas.95.2.525
发表时间：
1998-01-20
影响因子：
11.1
作者：
Hammarsten, O;Chu, G
通讯作者：
Chu, G
影响因子：
32.4
作者：
Blanchet FP;Moris A;Nikolic DS;Lehmann M;Cardinaud S;Stalder R;Garcia E;Dinkins C;Leuba F;Wu L;Schwartz O;Deretic V;Piguet V
通讯作者：
Piguet V