Transcription-replication conflicts trigger STING-mediated anti-tumor immunity following CDK12/13 inactivation [RNA-seq]
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ABSTRACT:
PROVIDER: PRJNA1191845 | ENA |
REPOSITORIES: ENA
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Project description:Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes an immunogenic molecular subtype of prostate cancer, marked by genomic instability and increased intratumoral T cell infiltration. However, the mechanisms underlying this phenotype and its therapeutic implications remain unclear. Here, we demonstrate that CDK12 inactivation or suppression of its paralog CDK13 activates stimulator of interferon genes (STING) signaling across multiple cancer types. Analysis of clinical cohorts receiving immune checkpoint blockade (ICB) revealed that reduced CDK12/13 expression correlates with improved survival and treatment response. Mechanistically, CDK12/13 depletion or targeted degradation induces transcription-replication conflicts and R-loop accumulation, triggering cytosolic DNA release and subsequent STING activation. Functionally, CDK12/13 degradation significantly delays tumor growth and exhibits synergistic effects with anti-PD1 therapy in various syngeneic tumor models. This combination enhances STING activity and promotes the infiltration and activation of CD8+ T cells within tumors. Notably, the anti-tumor effects of this combination require STING signaling and functional CD8+ T cells. These findings identify CDK12/13 as promising therapeutic targets for enhancing ICB efficacy, highlighting their potential to amplify STING-mediated anti-tumor immunity. This work provides a mechanistic framework for leveraging CDK12/13 antagonists in combination with ICB to improve clinical outcomes in cancer therapy.
2025-06-23 | GSE283227 | GEO
Project description:CDK12/13 inactivation triggers STING-mediated antitumor immunity in preclinical models
| PRJNA1192546 | ENA
Project description:Inactivation of cyclin-dependent kinase 12 (CDK12) characterizes an immunogenic molecular subtype of prostate cancer, marked by genomic instability and increased intratumoral T cell infiltration. However, the mechanisms underlying this phenotype and its therapeutic implications remain unclear. Here, we demonstrate that CDK12 inactivation or suppression of its paralog CDK13 activates stimulator of interferon genes (STING) signaling across multiple cancer types. Analysis of clinical cohorts receiving immune checkpoint blockade (ICB) revealed that reduced CDK12/13 expression correlates with improved survival and treatment response. Mechanistically, CDK12/13 depletion or targeted degradation induces transcription-replication conflicts and R-loop accumulation, triggering cytosolic DNA release and subsequent STING activation. Functionally, CDK12/13 degradation significantly delays tumor growth and exhibits synergistic effects with anti-PD1 therapy in various syngeneic tumor models. This combination enhances STING activity and promotes the infiltration and activation of CD8+ T cells within tumors. Notably, the anti-tumor effects of this combination require STING signaling and functional CD8+ T cells. These findings identify CDK12/13 as promising therapeutic targets for enhancing ICB efficacy, highlighting their potential to amplify STING-mediated anti-tumor immunity. This work provides a mechanistic framework for leveraging CDK12/13 antagonists in combination with ICB to improve clinical outcomes in cancer therapy.
2025-06-23 | GSE283088 | GEO
Project description:Immune checkpoint blockade (ICB) has obtained significant progress in treating multiple types of cancers, but its overall response rate and therapeutic efficacies are not yet satisfactory. To fulfil such needs, identification of combinational approach to enhance the therapeutic efficacies of ICB is highly demanded. The activation of cyclic GMP-AMP synthase-stimulator of interferon genes (cGAS-STING) signaling is critical to elicit the antitumor innate immune responses and a promising target to develop combinational immunotherapy. Accordingly, the application of STING agonist exhibits potent antitumor functions in preclinical models and is currently tested in clinical trials. However, deregulation of cGAS-STING is frequently observed in cancers and substantially attenuates the efficacies of treatments by harnessing cGAS-STING signaling. Hence, the underlying mechanisms of maintaining intracellular homeostasis of cGAS-STING need to be elucidated. Here we report the identification of PIKfyve as a negative regulator of cGAS-STING signaling. Inhibition of PIKfyve by kinase inhibitor YM201636 or genetic ablation markedly provokes the expression of cGAS-STING downstream IFN-stimulated genes (ISGs) and reschedules the antitumor microenvironment by recruiting CD8+ T lymphocytes. In melanoma models, PIKfyve inhibition confers sensitivity to the combinational therapy of cisplatin and anti-PD1, leading to a durable treatment response. Mechanistically, PIKfyve interacts with STING to promote its lysosomal degradation. These results highlight the importance of maintaining STING homeostasis as a direction to augment the efficacies of combinational immunotherapies
2025-05-05 | GSE218241 | GEO
Project description:Ionizing radiation promotes cytosolic DNA sensing and consequent antitumor immune responses. But how tumor cell-intrinsic cytosolic DNA sensing is initiated by radiation remains poorly defined. Here, we demonstrated that STING-mediated type I interferon production in tumor cells after radiation relied on the engagement of MLKL-mediated necroptosis, which was elicited by the ZBP1-RIPK3 signaling axis. Physiologically, tumor cell-intrinsic ZBP1-MLKL cascade augmented antitumor immune responses after radiation largely by regulating STING signaling. Mechanistically, ZBP1-MLKL-dependent necroptosis maintained the enrichment of mitochondria DNA inside the cytosol of tumor cells after radiation in a cell-density dependent fashion, contributing to type I interferon responses. In contrast, ablation of caspase-8 unleashed ZBP1-MLKL cascade to gain enhanced cytosolic DNA sensing, and in turn potentiated therapeutic effects of radiation. Thus, our findings uncover an unanticipated mechanism that ZBP1-MLKL-dependent necroptosis drives cytosolic DNA sensing-mediated antitumor immunity after radiation, and provide new strategy to improve radiotherapy by inhibiting caspase-8 cascade.
2021-10-13 | GSE168016 | GEO
Project description:Inflammatory diseases such as Aicardi-Goutieres Syndrome (AGS) and severe systemic lupus erythematosus (SLE) are generally lethal disorders that have been traced to defects in the exonuclease Trex1 (DNAseIII). Mice lacking Trex1 similarly die at an early age through comparable symptoms, including inflammatory myocarditis, through chronic activation of the STING (stimulator of interferon genes) pathway. Here we demonstrate that phagocytes rather than myocytes are predominantly responsible for causing inflammation, an outcome that could be alleviated following adoptive transfer of normal bone marrow into Trex1-/- mice. Trex1-/- macrophages did not exhibit significant augmented ability to produce pro-inflammatory cytokines compared to normal macrophages following exposure to STING-dependent activators, but rather appeared chronically stimulated by genomic DNA. These results shed molecular insight into inflammation and provide concepts for the design of new therapies. Total RNA obtained from wild type (WT), Trex1 deficient (TKO), STING deficient (SKO), or Trex1 and STING double deficient (STKO) mouse Heart
2014-07-09 | E-GEOD-59217 | biostudies-arrayexpress
Project description:We describe the epigenetic profiling of the H3K9me2 and HP1a in Drosophila third instar larvae before and after CDK12 depletion by RNA interference (RNAi). Here we show that CDK12 regulates heterochromatin dynamics in Drosophila chromosomes. Depletion of CDK12 induces the increased HP1a and H3K9me2 binding profile on the coding region of euchromatic genes, with the X chromosome being the most affected. These results are consistent with the polytene chromosome immunostaining pattern of HP1a and H3K9me2 after CDK12 knockdown in our initial cytological observations, which show that CDK12 depletion induce heterochromatin spreading on euchromatic arms, especially on the X chromosome. This study describes a novel role of the CDK12 complex in controlling the epigenetic transition between euchromatin and heterochromatin. Examination of the genome-wide H3K9me2 and HP1a binding profile in wildtype larvae (WT) and CDK12-depleted larvae (CDK12-KD). Examination of the genome-wide CDK12 binding profile in wildtype larvae (WT). Twelve independent immunoprecipitations were conducted for each antibody. Two biological replicates were performed.
2015-11-02 | E-GEOD-63011 | biostudies-arrayexpress
Project description:Inflammatory diseases such as Aicardi-Goutieres Syndrome (AGS) and severe systemic lupus erythematosus (SLE) are generally lethal disorders that have been traced to defects in the exonuclease Trex1 (DNAseIII). Mice lacking Trex1 similarly die at an early age through comparable symptoms, including inflammatory myocarditis, through chronic activation of the STING (stimulator of interferon genes) pathway. Here we demonstrate that phagocytes rather than myocytes are predominantly responsible for causing inflammation, an outcome that could be alleviated following adoptive transfer of normal bone marrow into Trex1-/- mice. Trex1-/- macrophages did not exhibit significant augmented ability to produce pro-inflammatory cytokines compared to normal macrophages following exposure to STING-dependent activators, but rather appeared chronically stimulated by genomic DNA. These results shed molecular insight into inflammation and provide concepts for the design of new therapies. Total RNA obtained from wild type murine embryonic fibroblasts (WT MEFs), Trex1 deficient MEFs (TKO) or STING and Trex1 double deficient MEFs (STKO) transfected with or without double strand DNA 90 (ISD) and examined cytokine production by these cells.
2014-07-09 | E-GEOD-59218 | biostudies-arrayexpress
Project description:In a forward genetic screen, we have previously identified a null mutant of Cdk12 that results in alterations in actin dynamics, the axon initial segment and electrophysiology in Drosophila melanogaster. To decipher how Cdk12 may be having these effects, we extracted RNA from pooled Drosophila heads and compared Cdk12-null mutants to controls at the transcriptome level.
2023-01-01 | E-MTAB-12090 | biostudies-arrayexpress
Project description:Despite progress in intensification of therapy, outcomes for patients with metastatic osteosarcoma (OS) have not improved in thirty years. We developed a system that enables preclinical screening of compounds against metastatic OS cells in the context of the native lung microenvironment. Using this strategy to screen a library of epigenetically-targeted compounds, we identified inhibitors of CDK12 to be most effective, reducing OS cell outgrowth in the lung by >90% at sub-micromolar doses. CDK12 inhibition led to defects in transcription elongation in a gene length- and expression-dependent manner. These effects were accompanied by defects in RNA processing and altered the expression of genes involved in transcription regulation and the DNA damage response. We further identify OS models that differ in their sensitivity to CDK12 inhibition in the lung and provide evidence that upregulated MYC levels may mediate these differences. Our studies provide a framework for rapid preclinical testing of compounds with anti-metastatic activity and highlight CDK12 as a potential therapeutic target in osteosarcoma.
2019-06-06 | GSE132233 | GEO