Triple-negative breast cancer cells rely on kinase-independent functions of CDK8 to evade NK-cell-mediated tumor surveillance
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ABSTRACT:
PROVIDER: PRJNA676144 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR13036442.fastq.gz | Fastqsanger.gz | |||
| SRR13036443.fastq.gz | Fastqsanger.gz | |||
| SRR13036444.fastq.gz | Fastqsanger.gz | |||
| SRR13036445.fastq.gz | Fastqsanger.gz | |||
| SRR13036446.fastq.gz | Fastqsanger.gz |
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Project description:Triple-negative breast cancer (TNBC) is an aggressive malignant disease that is responsible for approximately 15% of breast cancers. The standard of care relies on surgery and chemotherapy but the prognosis is poor and there is an urgent need for new therapeutic strategies. Recent in silico studies have revealed an inverse correlation between recurrence-free survival and the level of cyclin- dependent kinase 8 (CDK8) in breast cancer patients. CDK8 is known to have a role in natural killer (NK) cell cytotoxicity, but its function in TNBC progression and immune cell recognition or escape has not been investigated. We have used a murine model of orthotopic breast cancer to study the tumor-intrinsic role of CDK8 in TNBC. Knockdown of CDK8 in TNBC cells impairs tumor regrowth upon surgical removal and prevents metastasis. In the absence of CDK8, the epithelial-to-mesenchymal transition (EMT) is impaired and immune-mediated tumor-cell clearance is facilitated. CDK8 drives EMT in TNBC cells in a kinase-independent manner. In vivo experiments have confirmed that CDK8 is a crucial regulator of NK-cell-mediated immune evasion in TNBC. The studies also show that CDK8 is involved in regulating the checkpoint inhibitor programmed death-ligand 1 (PD-L1). The CDK8–PD-L1 axis is found in mouse and human TNBC cells, underlining the importance of CDK8-driven immune cell evasion in these highly aggressive breast cancer cells. Our data link CDK8 to PD-L1 expression and provide a rationale for investigating the possibility of CDK8-directed therapy for TNBC.
2021-10-21 | GSE161295 | GEO
Project description:Triple-negative breast cancer (TNBC) is an aggressive malignant disease that is responsible for approximately 15% of breast cancers. The standard of care relies on surgery and chemotherapy but the prognosis is poor and there is an urgent need for new therapeutic strategies. Recent in silico studies have revealed an inverse correlation between recurrence-free survival and the level of cyclin-dependent kinase 8 (CDK8) in breast cancer patients. CDK8 is known to have a role in natural killer (NK) cell cytotoxicity, but its function in TNBC progression and immune cell recognition or escape has not been investigated. We have used a murine model of orthotopic breast cancer to study the tumor-intrinsic role of CDK8 in TNBC. Knockdown of CDK8 in TNBC cells impairs tumor regrowth upon surgical removal and prevents metastasis. In the absence of CDK8, the epithelial-to-mesenchymal transition (EMT) is impaired and immune-mediated tumor-cell clearance is facilitated. CDK8 drives EMT in TNBC cells in a kinase-independent manner. In vivo experiments have confirmed that CDK8 is a crucial regulator of NK-cell-mediated immune evasion in TNBC. The studies also show that CDK8 is involved in regulating the checkpoint inhibitor programmed death-ligand 1 (PD-L1). The CDK8-PD-L1 axis is found in mouse and human TNBC cells, underlining the importance of CDK8-driven immune cell evasion in these highly aggressive breast cancer cells. Our data link CDK8 to PD-L1 expression and provide a rationale for investigating the possibility of CDK8-directed therapy for TNBC.
| S-EPMC8542046 | biostudies-literature
Project description:Quiescent tissue stem cells evade immune surveillance
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Project description:The Mediator kinase module regulates eukaryotic transcription by phosphorylating transcription-related targets and by modulating the association of Mediator and RNA Polymerase II. The activity of its catalytic core, cyclin-dependent kinase 8 (CDK8), is controlled by Cyclin C and MED12, with its deregulation contributing to numerous malignancies. Here, we combine in vitro biochemistry, crosslinking coupled to mass spectrometry and in vivo studies to describe the binding location of the N-terminal segment of MED12 on the CDK8/Cyclin C complex and to gain mechanistic insights into the activation of CDK8 by MED12. Our data demonstrate that the N-terminal portion of MED12 wraps around CDK8, whereby it positions an "activation helix" close to the T-loop of CDK8 for its activation. Intriguingly, mutations in the activation helix that are frequently found in cancers do not diminish the affinity of MED12 for CDK8, yet likely alter the exact positioning of the activation helix. Furthermore, we find the transcriptome-wide gene expression changes in human cells that result from a mutation in the MED12 activation helix to correlate with deregulated genes in breast and colon cancer. Last, functional assays in presence of kinase inhibitors reveal that binding of MED12 remodels the active site of CDK8 and thereby precludes the inhibition of ternary CDK8 complexes by type-II kinase inhibitors. Taken together, our results not only allow us to propose a revised model of how CDK8 activity is regulated by MED12, but they also offer a path forward in developing small molecules that target CDK8 in its MED12-bound form.
2020-01-04 | GSE135458 | GEO
Project description:We use biochemically reconstituted transcription initiation components including the Mediator core and Cdk8 kinase modules (CKM) to investigate the function of the CKM in regulating the Mediator-RNA polymerase II interaction in a highly purified system. We use cross-linking coupled to mass spectrometry to map the interaction of the CKM and core Mediator, and in vitro phosphorylation assays followed by phosphopeptide enrichment coupled to mass spectrometry to identify Cdk8 phosphorylation targets in this context and biochemically dissect their functions. Finally, we investigate the function of phosphorylation by Cdk8 on transcription in vivo. Based on that, we propose a model to integrate the phosphorylation-dependent and -independent functions of the CKM in transcription initiation.
2021-04-28 | PXD023361 | Pride
Project description:Mogat1 drives metabolic adaptations to evade immune surveillance
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Project description:We present a novel mathematical model involving various immune cell populations and tumor cellpopulations. The model describes how tumor cells evolve and survive the brief encounter with theimmune system mediated by natural killer (NK) cells and the activated CD8þcytotoxic T lymphocytes(CTLs). The model is composed of ordinary differential equations describing the interactions betweenthese important immune lymphocytes and various tumor cell populations. Based on up-to-dateknowledge of immune evasion and rational considerations, the model is designed to illustrate how tu-mors evade both arms of host immunity (i.e.innate and adaptive immunity). The model predicts that(a) an influx of an external source of NK cells might play a crucial role in enhancing NK-cell immunesurveillance; (b) the host immune system alone is not fully effective against progression of tumor cells;(c) the development of immunoresistance by tumor cells is inevitable in tumor immune surveillance. Ourmodel also supports the importance of infiltrating NK cells in tumor immune surveillance, which can beenhanced by NK cell-based immunotherapeutic approaches.
2020-03-20 | MODEL2003040001 | BioModels
Project description:Stem cells are critical for the maintenance of many tissues, and thus their integrity is crucial, but whether this integrity is maintained in the face of an immune response is not well defined. Here we set out to determine the outcome of T cell interactions with adult stem cells in their physiological niche. We find that fast cycling epithelial stem cells, including Lgr5+ intestinal stem cells, as well as ovary and mammary stem cells, are eliminated by activated T-cells, but slow cycling stem cells, specifically hair follicle and muscle stem cells, are resistant to T-cell killing. This is an intrinsic property of the quiescent stem cells resulting from systemic downregulation of the antigen presentation machinery, including MHC class I, Tap proteins, and the transactivator Nlrc5, which is reversed upon stem cell entry into the cell cycle. These findings identify a link between tissue stem cell quiescence, antigen presentation, and immune evasion, and may help explain why mutations in long-lived stem cells would not lead to immune editing. They also suggest how cancer-initiating cells may evade immune surveillance
2018-04-01 | GSE109574 | GEO
Project description:The Cdk8 kinase module (CKM) is a dissociable part of the coactivator complex Mediator that regulates RNA polymerase II (Pol II transcription. The CKM has negative and positive functions in gene transcription that remain poorly understood at the mechanistic level. Here, we prepare recombinant CKM from the yeast Saccharomyces cerevisiae and show that it binds core Mediator (cMed) to sterically inhibit cMed binding to the Pol II preinitiation complex (PIC) in vitro. We further show that the Cdk8 kinase activity of CKM counteracts CKM-cMed interaction,thereby releasing CKM and enabling Mediator to bind the PIC. Finally, we report that the kinase activity of Cdk8 is required for gene activation during heat shock in vivo, but not under steady state growth conditions. These results converge with previous literature on a model for CKM function. In this model, CKM negatively regulates Mediator function at upstream activating sequences by preventing Mediator binding to the PIC at the promoter. During gene activation, Cdk8 kinase activity may release Mediator and allow its binding to the PIC, thereby stimulating transcription initiation and accounting for the positive function of CKM.
2021-06-16 | GSE161140 | GEO
Project description:CDK8 Mediator kinase is amplified and overexpressed in colon cancers; elevated CDK8 expression is associated with shorter patient survival. Nevertheless, CDK8 kinase inhibitors do not generally suppress colon cancer growth. We addressed this paradox by investigating the effects of CDK8 knockdown or a CDK8 kinase inhibitor on tumor growth at primary and metastatic sites. CDK8 knockdown or inhibition had no significant effect on primary tumors but suppressed the growth of hepatic metastases in murine and human colon cancer models. The effect of CDK8 inhibition on liver metastasis is mediated by upregulation of matrix metalloproteinase (MMP) inhibitor TIMP3 and downregulation of several MMPs.
2017-10-16 | GSE104963 | GEO