BV6 induces an early wave of gene expression via NF-κB and AP-1 and a second wave via TNFα/TNFR1 signaling
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ABSTRACT:
PROVIDER: PRJNA421923 | ENA |
REPOSITORIES: ENA
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Project description:Smac mimetics are considered as promising cancer therapeutics, but little is yet known about how they alter gene expression. In this study we used an unbiased genome-wide expression array to investigate Smac mimetic BV6-induced gene regulation in breast cancer cell lines. Kinetic analysis revealed that BV6 alters gene expression in two waves. The first wave primarily involves NF-κB- and AP-1 families of transcription factors, while the second wave largely depends on tumor necrosis factor receptor 1 (TNFR1) signaling. Interestingly, disrupting auto-/paracrine tumor necrosis factor-α (TNFα)/ (TNFR1) signaling by knockdown of TNFR1 strongly attenuates the BV6-induced second wave of gene expression and upregulation of many pathways including NF-κB signaling, apoptosis and immune signalling, but not MAPK signaling pathways. Consistently, BV6 stimulates phosphorylation of cJun, a marker of MAPK cascade activation, irrespective of the presence or absence of the TNFα blocking antibody Enbrel. We show here in a comprehensive overview that BV6-induced gene expression in breast cancer cells takes place in a time- as well as TNFR1-dependent manner.
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Project description:Acute pancreatitis (AP) is an inflammatory disorder of the pancreas that can progress to systemic inflammatory response syndrome and multiple organ failure with high mortality. TNFα (tumor necrosis factor-alpha), a key proinflammatory cytokine elevated in early AP, triggers both pancreatic inflammation and acinar cell apoptosis through TNFR1 (tumor necrosis factor-alpha receptor 1) binding. However, the predominant pathological mechanism of TNFα/TNFR1 axis in AP - whether primarily mediating inflammatory responses or apoptotic pathways - remains unclear. To elucidate the precise cellular mechanisms through which Tnfr1 deficiency modulates inflammation, we employed scRNA-seq to comprehensively characterize transcriptomic alterations at single-cell resolution.
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Project description:TNFα is an proinflammatory cytokine that can mediate immunosuppressive effects in cancer. Tumors in which we silenced TNFR1 by CRISPR/Cas9 showed disability of the TNFR1 KO variants to engraft in immunocompetent hosts, whilst engraftment in immunodeficient or CD8 T lymphocyte-depleted mice was preserved. The mechanism was mediated by secondary chemotactic inflammatory mediators elicited by TNFα in the malignant cells themselves. As a result, TNFR1 KO variants recruited drastically fewer myeloid-derived suppressor cells into the tumor microenvironment, thus explaining the immune escape of the WT variants. Interestingly, small amounts of TNFR1-sufficient tumor cells co-engrafted with the TNFR1 KO variants rescued tumorigenicity in the same tumor lesion but not in a distantly implanted TNFR1 KO tumor. Secondary mediators chiefly include CXCR1/2-acting chemokines, prostaglandin-E2 and TNFα itself. Knocking-down TNFR1 in a human tumor cell line rendered comparable results when xenografted. Analyses of scRNA-seq and spatial transcriptomics datasets from human solid tumors corroborate the role of TNFR1 on tumor cells in the induction of secondary pro-tumor inflammatory mediators.
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Project description:Targeting the TNFα/TNFR1 axis to alleviate inflammation in experimental acute pancreatitis
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Project description:TNFα reportedly mediates multiple protumor and immunosuppressive functions acting on stromal cells in cancer-bearing hosts as a result of enhancing activation immune cell death of T lymphocytes, causing dysfunction of dendritic cells and/or eliciting chemokines which attract myeloid-derived suppressor cells. Experiments performed in transplantable tumors in which we silenced TNFR1 with CRISPR/Cas9 showed the inability of the TNFR1 KO variants to engraft in immunocompetent hosts, whilst engraftment in immunodeficient or CD8 T lymphocyte-depleted mice was preserved. The mechanism was related to secondary inflammatory mediators elicited by TNFα in malignant cells themselves, including CXCR1/2 chemokines and interestingly TNFα itself. As a result, TNFR1 KO variants recruited drastically fewer myeloid-derived suppressor cells into the tumor microenvironment, thus explaining the immune escape of the WT variants. Interestingly, TNFR1-sufficient tumor cells, when co-engrafted with the TNFR1 KO variants, rescued tumorigenicity of the same tumor lesion but not of a distantly implanted TNFR1 KO tumor. Secondary mediators chiefly include CXCR1/2-acting chemokines and prostaglandin E2 synthetase. Similar effects were observed upon knocking-down TNFR1 in a human tumor cell line. Moreover, human TNFR1 KO HT29 variants, when xenografted in immunodeficient mice, released lower levels of CXCL8 (IL-8) and recruited fewer murine myeloid cells into the tumor microenvironment. Analyses of scRNAseq data sets from human solid tumors corroborate the role of TNFR1 on tumor cells to induce secondary proinflammatory mediators. All together, we provide evidence for an essential role of TNFR1 expressed on the surface of tumor cells in immunoscape and further support TNF neutralization in the clinic to improve the efficacy and safety of approved immunotherapy approaches.
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Project description:TNFα reportedly mediates multiple protumor and immunosuppressive functions acting on stromal cells in cancer-bearing hosts as a result of enhancing activation immune cell death of T lymphocytes, causing dysfunction of dendritic cells and/or eliciting chemokines which attract myeloid-derived suppressor cells. Experiments performed in transplantable tumors in which we silenced TNFR1 with CRISPR/Cas9 showed the inability of the TNFR1 KO variants to engraft in immunocompetent hosts, whilst engraftment in immunodeficient or CD8 T lymphocyte-depleted mice was preserved. The mechanism was related to secondary inflammatory mediators elicited by TNFα in malignant cells themselves, including CXCR1/2 chemokines and interestingly TNFα itself. As a result, TNFR1 KO variants recruited drastically fewer myeloid-derived suppressor cells into the tumor microenvironment, thus explaining the immune escape of the WT variants. Interestingly, TNFR1-sufficient tumor cells, when co-engrafted with the TNFR1 KO variants, rescued tumorigenicity of the same tumor lesion but not of a distantly implanted TNFR1 KO tumor. Secondary mediators chiefly include CXCR1/2-acting chemokines and prostaglandin E2 synthetase. Similar effects were observed upon knocking-down TNFR1 in a human tumor cell line. Moreover, human TNFR1 KO HT29 variants, when xenografted in immunodeficient mice, released lower levels of CXCL8 (IL-8) and recruited fewer murine myeloid cells into the tumor microenvironment. Analyses of scRNAseq data sets from human solid tumors corroborate the role of TNFR1 on tumor cells to induce secondary proinflammatory mediators. All together, we provide evidence for an essential role of TNFR1 expressed on the surface of tumor cells in immunoscape and further support TNF neutralization in the clinic to improve the efficacy and safety of approved immunotherapy approaches.
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