Neutrophils recruited by NKX2-1 suppression via activation of CXCLs/CXCR2 axis promote lung adenocarcinoma progression
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ABSTRACT:
PROVIDER: PRJNA1126625 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR29487482_1.fastq.gz | Fastqsanger.gz | |||
| SRR29487482_2.fastq.gz | Fastqsanger.gz | |||
| SRR29487483_1.fastq.gz | Fastqsanger.gz | |||
| SRR29487483_2.fastq.gz | Fastqsanger.gz | |||
| SRR29487484_1.fastq.gz | Fastqsanger.gz |
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Project description:Background: Lung adenocarcinoma (LUAD) progression is dependent on the immune tumor microenvironment through paracrine signaling. Lineage-specific transcription NKX2-1 is a well-developed pathology marker to define LUAD with progressive impact in patients. However, the involvement of NKX2-1 in modeling the tumor immune microenvironment is still unclear. Here, we demonstrated that NKX2-1-low tumors expedite tumor progression in LUAD through increased tumor-promoting neutrophils. Method: Single-cell RNA sequencing and Visium in situ capturing profiling were used to characterize the infiltration of neutrophils in NKX2-1-low LUAD tumors at high resolution. Clinical relevance of NKX2-1 expression and disease status were evaluated by immunohistochemical analysis of LUAD tissue arrays and the overall survival analysis was performed by TCGA databases. qRT-PCR validated the level of CXC chemokines, and proinflammatory genes in LUAD cells, meanwhile chemokine array confirmed the secretion of chemokines. Mechanistically, ATAC-seq was used to confirm the modulatory role of NKX2-1 on the chromatin accessibility of CXC chemokine genes. Results: NKX2-1 downregulation was observed in high-grade LUAD with increased neutrophil recruitment and infiltration. NKX2-1 knockdown promoted the expression and secretion of CXCL1, CXCL2, CXCL3, and CXCL5 in LUAD cells. Mechanistically, ATAC-seq revealed the restrictive regulation of NKX2-1 on the promoters of CXCL1, CXCL2 and CXCL5. Single-cell RNA sequencing and Visium in situ capturing revealed the infiltrated neutrophil had strong cell-cell communication through the activation of CXCLs/CXCR2 signaling with increased tumor growth and vice versa when inhibited with CXCR2 antagonist SB225002. Conclusion: This study revealed that NKX2-1 negatively regulates the infiltration of tumor-promoting neutrophils by suppressing CXCLs/CXCR2-dependent mechanisms. Hence, targeting CXCR2 in NKX2-1-low tumors is a potential antitumor therapy that improves LUAD patient outcomes.
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Project description:NK2 Homeobox 1 (NKX2-1) is a well-characterized pathological marker that delineates lung adenocarcinoma (LUAD) progression. The advancement of LUAD is influenced by the immune tumor microenvironment through paracrine signaling. However, the involvement of NKX2-1 in modeling the tumor immune microenvironment is still unclear. Here, the downregulation of NKX2-1 is observed in high-grade LUAD. Meanwhile, single-cell RNA sequencing and Visium in situ capturing profiling revealed the recruitment and infiltration of neutrophils in orthotopic syngeneic tumors exhibiting strong cell-cell communication through the activation of CXCLs/CXCR2 signaling. The depletion of NKX2-1 triggered the expression and secretion of CXCL1, CXCL2, CXCL3, and CXCL5 in LUAD cells. Chemokine secretion is analyzed by chemokine array and validated by qRT-PCR. ATAC-seq revealed the restrictive regulation of NKX2-1 on the promoters of CXCL1, CXCL2, and CXCL5 genes. This phenomenon led to increased tumor growth, and conversely, tumor growth decreased when inhibited by the CXCR2 antagonist SB225002. This study unveils how NKX2-1 modulates the infiltration of tumor-promoting neutrophils by inhibiting CXCLs/CXCR2-dependent mechanisms. Hence, targeting CXCR2 in NKX2-1-low tumors is a potential antitumor therapy that may improve LUAD patient outcomes.
| S-EPMC11481344 | biostudies-literature
Project description:Targeting neutrophils has emerged as a promising therapeutic strategy for various inflammatory diseases. Here, we investigate a highly specific monoclonal antibody that targets CXCR2, which is a major chemokine receptor on neutrophils. This antibody functions as an inverse agonist, binds tightly to CXCR2 in a mutually exclusive manner versus IL-8, and completely blocks CXCR2-β-arrestin signaling and subsequent neutrophil functions. Treatment with the antibody appears to result in an overall reversal of IL-8 induced gene expressions in primary human neutrophils. The antibody demonstrates remarkable efficacy in controlling dysregulated neutrophil activity in peripheral circulation and inflammatory tissues in four inflammation animal models. In addition, administration of the antibody not only ameliorates the symptoms of neutrophilia, but also mitigates tissue damage in cases of acute lung inflammation and delayed-type-hypersensitivity reactions. We also checked the effects of the antibody on human neutrophils activated by the natural ligand IL-8 or not in vitro through RNAseq.
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2024-10-03 | GSE245864 | GEO
Project description:The NKX2-1 transcription factor, a regulator of normal lung development, is the most significantly amplified gene in human lung adenocarcinoma. To better understand how genomic alterations of NKX2-1 drive tumorigenesis, we generated an expression signature associated with NKX2-1 amplification in human lung adenocarcinoma, and analyzed DNA binding sites of NKX2-1 by genome-wide chromatin immunoprecipitation from NKX2-1-amplified human lung adenocarcinoma cell lines. Combining these expression and cistromic analyses identified LMO3, itself encoding a transcription regulator, as a candidate direct transcriptional target of NKX2-1, in addition to consensus binding motifs including a nuclear hormone receptor signature and a Forkhead box motif in NKX2-1-bound sequences. RNA interference analysis of NKX2-1-amplified cells compared to non-amplified cells demonstrated that LMO3 mediates cell proliferation downstream of NKX2-1; cistromic analysis that NKX2-1 may cooperate with FOXA1. Our findings provide new insight into the transcriptional regulatory network of NKX2-1 and suggest that LMO3 is a transducer of lineage specific cell survival of NKX2-1-amplified lung adenocarcinomas. NCI-H2009 cells with stable expression of either pLKO-Tet-Op-shGFP (n=4) or pLKO-Tet-Op-shNKX2-1 (pooled population; n=3 and a clone; n=3) were treated with 50ng/ml of doxycyline for 48 hours. Total RNA was extracted, gene expression profiling was performed and differential gene expression between shGFP and shNKX2-1 was analyzed to determine the effects by suppression of NKX2-1 in NCI-H2009 cells.
2013-04-15 | E-GEOD-40270 | biostudies-arrayexpress
Project description:Effect of alternative CXCR2 ligands on human neutrophils in vitro
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Project description:[Background] TNFa-induced adipose-related protein (TIARP) is a six-transmembrane protein that is expressed on macrophages, neutrophils and synoviocytes. We have recently reported that TIARP deficient mice (TIARP-/-) spontaneously developed arthritis, and had the high susceptibility to collagen-induced arthritis (CIA) with enhanced interleukin (IL)-6 production. However, the effect of TIARP to neutrophils and fibroblast-like syonoviocytes (FLS) has not been clearly elucidated. [Methods] We analyzed the roles of TIARP in K/BxN serum transfer model using TIARP-/- mice. We characterized the differences of neutrophils between WT and TIARP-/- mice by DNA microarray. Transmigration assays of TIARP-/- neutrophils were performed in vitro and in vivo. FLS were cultured with TNF? and the production of CXCL2 (a specific ligand of CXCR1 and CXCR2) and IL-6 were measured by ELISA. Moreover, TIARP-/- mice transferred with K/BxN serum were treated with anti-IL-6R antibodies. [Results] Arthritis in TIARP-/- mice transferred with K/BxN serum was significantly exacerbated. We identified overexpression of CXCR1 and CXCR2 in TIARP-/- neutrophils by DNA microarray. Neutrophils from TIARP-/- mice showed strong migration activity. The enhancement of chomotactic activity of TIARP-/- neutrophil was greatly facilitated by CXCL2 in vitro and in vivo. In addition, TIARP-/-FLS has enhanced the production of CXCL2 and IL-6 and the cell proliferation in the presence of TNFa, and the blockade of IL-6R significantly attenuated arthritis in vivo. [Conclusion] Our findings indicate that TIARP might down-regulate the production of CXCL2 and IL-6 in FLS, and the expression of chemokine receptors (CXCR1 and CXCR2) in neutrophils, resulting in the protective ability of neutrophils migration into arthritic joints. Mice were treated with thiogycollate medium intraperitoneally. After 3 days, peritoneal macrophages were isolated from three WT or TIARP-deficient mice, and these cells were stimulated by TNF? for 24 hours. Ly6G+ Neutrophils were isolated from splenocytes by MACS.
2015-09-23 | E-GEOD-73306 | biostudies-arrayexpress
Project description:CXCR2 intrinsically drives the maturation and function of neutrophils in mice
| PRJNA862728 | ENA