Caspase-1 from Human Myeloid Derived Suppressor Cells Can Promote T-cell independent Tumor Proliferation
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ABSTRACT:
PROVIDER: PRJNA447932 | ENA |
REPOSITORIES: ENA
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Project description:Immunosuppressive myeloid-derived suppressive cells (MDSCs) are characterized by their phenotypic and functional heterogeneity. To better define their T cell-independent functions within the tumor, sorted monocytic CD14+CD11b+HLA-DRlow/- MDSCs (mMDSCs) from squamous cell carcinoma patients showed upregulated caspase-1 activity, that was associated with increased IL1b and IL18 expression. In vitro studies demonstrated that mMDSCs promoted caspase-1-dependent proliferation of multiple squamous carcinoma cell lines in both human and murine systems. In vivo, growth rates of B16, MOC1, and Panc02 were significantly blunted in chimeric mice adoptively transferred with caspase-1 null bone marrow cells under T cell-depleted conditions. Adoptive transfer of wildtype Gr-1+CD11b+ MDSCs from tumor-bearing mice reversed this antitumor response, whereas caspase-1 inhibiting thalidomide-treated MDSCs phenocopied the antitumor response found in caspase-1 null mice. We further hypothesized that MDSC caspase-1 activity could promote tumor intrinsic MyD88-dependent carcinogenesis. In mice with wildtype caspase-1, MyD88-silenced tumors displayed reduced growth rate, but in chimeric mice with caspase-1 null bone marrow cells, MyD88-silenced tumors did not display differential tumor growth rate. When we queried the TCGA database, we found that caspase-1 expression is correlated with overall survival in squamous cell carcinoma patients. Taken together, our findings demonstrated that caspase-1 in MDSCs is a direct T cell-independent mediator of tumor proliferation.
2021-03-02 | GSE112481 | GEO
Project description:HOXB-AS3 expressions promote cell proliferation
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Project description:Caspase-1 signaling in myeloid suppressor cells can promote T-cell independent cancer progression, but the regulation of inflammasome signaling within the highly heterogeneous myeloid cells in the tumor milieu remains elusive. To resolve this complexity, scRNA-seq of human head & neck carcinoma identified distinct inflammasome complex genes within specific clusters of tumor-infiltrating myeloid cells. Among these myeloid cells, NLRP3 sensor and downstream effector IL-1β transcripts were enriched in multiple monocytic and macrophage subtypes in the TME. In vivo, we showed that NLRP3, and not AIM2, phenocopied the caspase-1/IL-1β dependent tumor progression. Paradoxically, we found that myeloid-intrinsic caspase-1 signaling within the TME increased myeloid survival without significant intratumoral trafficking as would be predicted from their canonical pyroptotic function. Mechanistically, this myeloid NLRP3/IL-1β signaling axis promotion of tumor growth was found to be gasdermin D independent. When we probed for the tumor intrinsic factors that regulated NLRP3/IL-1β signaling, we found that mononuclear phagocyte-mediated efferocytosis of dying tumor cells in the TME directly activated NLRP3 dependent inflammasome signaling to drive IL-1β secretion and to promote tumor growth. Dynamic RNA velocity analysis of the single cell transcriptomic dataset showed a strong directional flow from efferocytosis gene-sethigh macrophages to an inflammasome gene-sethigh macrophage population. Cumulatively, we provide a novel inflammasome signaling axis between tumor apoptosis and myeloid cells that characterizes chronic inflammation induced malignancy.
2022-04-13 | GSE200560 | GEO
Project description:Mutation in nucleophosmin (NPM1) causes relocalization of this normally nucleolar protein to the cytoplasm (NPM1c+). Despite NPM1 mutation being the most common driver mutation in cytogenetically normal adult acute myeloid leukemia (AML), the mechanisms of NPM1c+-induced leukemogenesis remain unclear. Caspase-2 is a pro-apoptotic protein activated by NPM1 in the nucleolus. Here, we show that caspase-2 is also activated by NPM1c+ in the cytoplasm and DNA damage-induced apoptosis is caspase-2-dependent in NPM1c+ but not in NPM1wt AML cells. Strikingly, in NPM1c+ cells, caspase-2 loss results in profound cell cycle arrest, differentiation, and down-regulation of stem cell pathways that regulate pluripotency including impairment in the AKT/mTORC1 and Wnt signaling pathways, and inhibition of Rictor cleavage. In contrast, there were minimal differences in proliferation, differentiation, or the transcriptional profile of NPM1wt cells lacking caspase-2. Our results show that caspase-2 is essential for proliferation and self-renewal of AML cells expressing mutated NPM1. This study demonstrates that caspase-2 is a major effector of NPM1c+ function.
2024-04-17 | GSE249545 | GEO
Project description:MCPyV targets NDRG1 to promote cellular proliferation
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Project description:Myeloid-derived suppressor cells promote lung cancer metastasis
| PRJNA564103 | ENA
Project description:Formation of the Death-Inducing Signalling Complex (DISC) initiates the extrinsic apoptotic signalling cascade. Caspase-8 and its regulator cFLIP control death signalling by binding to the receptor via DISC-bound FADD. By elucidating the function of Caspase-10, a close homologue of caspase-8, we unexpectedly found that caspase-10 negatively regulates caspase-8-mediated cell death signalling in the DISC. We demonstrate that caspase-10 inhibits the activation of caspase-8 independent of cFLIP. Furthermore, we show that caspase-8 does not compete with other tandem DED proteins such as cFLIP or caspase-10 in binding via FADD to the receptor as current models suggest. By utilizing caspase-8 knockout cells, we demonstrate that caspase-8 has to be placed upstream of both cFLIP and caspase-10 in the DISC. We further show that DISC formation and/or stability depends on caspase-8 but is independent from its enzymatic activity. Surprisingly, we identified caspase-10 to rewire DISC-signalling to NF-kB activation and cell survival. Our data are consistent with a model in which caspase-10 and cFLIP co-ordinately regulate caspase-8-mediated cell death signalling.
2016-04-20 | GSE75365 | GEO
Project description:Purpose: Next-generation sequencing (NGS) has revolutionized systems-based analysis of cellular pathways. The goals of this study are using RNA sequencing analysis to test the effects of overexpressing caspase-8 mutants or wild-type caspase-8 on the mRNA of KYSE150 cells. Methods: KYSE150 cells were transfected with caspase-8 mutants or wild-type caspase-8 for 48 hours in 1640 medium plus 10% serum. Two independent replicates were plated, transfected in parallel for each caspase-8 mutants or wild-type caspase-8. Results: Log-fold changes of mRNAs between caspase-8 mutants and wild-type caspase-8 group were selected with a significance threshod of p<0.05. There are 3974 overlapping differentially expressed genes in the caspase-8 mutant cells compared to the wild-type caspase-8 cells. Conclusions: Our study determined the mRNA changes of caspase-8 mutant KYSE150 cells compared to the wild-type caspase-8 cells.
2022-03-17 | GSE198569 | GEO
Project description:Human mutations in the death receptor Fas or its ligand FasL cause autoimmune lymphoproliferative syndrome (ALPS), whereas mutations in caspase-8 or its adaptor FADD â which mediate cell death downstream of Fas/FasL â cause severe immunodeficiency in addition to ALPS. Mouse models have corroborated a role for FADD-caspase-8 in promoting inflammatory responses, but the mechanisms underlying immunodeficiency remain undefined. Here, we identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production that is cleaved and inactivated by caspase-8. N4BP1 deletion in mice significantly increased production of select cytokines upon Toll-like receptor (TLR) 1/2, TLR7, or TLR9 stimulation, but not upon TLR3 or TLR4 engagement. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, impaired TLR3 and TLR4 cytokine responses of caspase-8-deficient macrophages were largely rescued by co-deletion of N4BP1. Thus, persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumor necrosis factor (TNF), like TLR3 or TLR4 agonists, also induced caspase-8-dependent cleavage of N4BP1, thereby licensing TRIF-independent TLRs to produce higher levels of inflammatory cytokines. Illustrating the importance of this function of TNF in vivo, TNF blockade increased the mortality of mice infected with Streptococcus Pneumoniae, but did not do so when infected mice lacked N4BP1. Collectively, our results identify N4BP1 as a potent suppressor of cytokine responses; reveal N4BP1 cleavage by Caspase-8 as a point of signal integration during inflammation; and offer an explanation for immunodeficiency caused by FADD-caspase-8 mutations.
2020-09-10 | GSE157786 | GEO
Project description:Human mutations in the death receptor Fas or its ligand FasL cause autoimmune lymphoproliferative syndrome (ALPS), whereas mutations in caspase-8 or its adaptor FADD â which mediate cell death downstream of Fas/FasL â cause severe immunodeficiency in addition to ALPS. Mouse models have corroborated a role for FADD-caspase-8 in promoting inflammatory responses, but the mechanisms underlying immunodeficiency remain undefined. Here, we identify NEDD4-binding protein 1 (N4BP1) as a suppressor of cytokine production that is cleaved and inactivated by caspase-8. N4BP1 deletion in mice significantly increased production of select cytokines upon Toll-like receptor (TLR) 1/2, TLR7, or TLR9 stimulation, but not upon TLR3 or TLR4 engagement. N4BP1 did not suppress TLR3 or TLR4 responses in wild-type macrophages owing to TRIF- and caspase-8-dependent cleavage of N4BP1. Notably, impaired TLR3 and TLR4 cytokine responses of caspase-8-deficient macrophages were largely rescued by co-deletion of N4BP1. Thus, persistence of intact N4BP1 in caspase-8-deficient macrophages impairs their ability to mount robust cytokine responses. Tumor necrosis factor (TNF), like TLR3 or TLR4 agonists, also induced caspase-8-dependent cleavage of N4BP1, thereby licensing TRIF-independent TLRs to produce higher levels of inflammatory cytokines. Illustrating the importance of this function of TNF in vivo, TNF blockade increased the mortality of mice infected with Streptococcus Pneumoniae, but did not do so when infected mice lacked N4BP1. Collectively, our results identify N4BP1 as a potent suppressor of cytokine responses; reveal N4BP1 cleavage by Caspase-8 as a point of signal integration during inflammation; and offer an explanation for immunodeficiency caused by FADD-caspase-8 mutations.
2020-09-09 | GSE148066 | GEO