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KDM6A loss recruits tumor-associated neutrophils and promotes neutrophil extracellular trap formation via the CXCL1-CXCR2 axis in pancreatic cancer

ABSTRACT: KDM6A loss recruits tumor-associated neutrophils and promotes neutrophil extracellular trap formation via the CXCL1-CXCR2 axis in pancreatic cancer

PROVIDER: PRJNA837575 | ENA |

REPOSITORIES: ENA

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KDM6A loss recruits tumor-associated neutrophils and promotes neutrophil extracellular trap formation via the CXCL1-CXCR2 axis in pancreatic cancer

Project description:Lysine (K)-specific demethylase 6A (KDM6A) is a frequently mutated tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC). However, how KDM6A loss impacts PDAC tumor immune microenvironment is not known. Tumor-associated neutrophils (TANs) and neutrophil extracellular traps (NETs) in the tumor microenvironment contribute to PDAC progression. This study used genetically engineered pancreas-specific Kdm6a-knockout PDAC mouse model and human PDAC tissue samples to demonstrate that KDM6A loss correlates with increased TANs and NETs formation. Genome-wide Bru-seq analysis showed that the expression of many chemotactic cytokines, especially CXC motif chemokine ligand 1 (CXCL1), were upregulated in KDM6A-knockout PDAC cells. We confirmed that KDM6A-deficient PDAC cells secreted higher levels of CXCL1 protein, which in turn recruits neutrophils. Furthermore, the CXCL1 neutralizing antibody blocked the chemotactic and NETs-promoting property of KDM6A-deficient PDAC cells and tumor growth in a syngeneic orthotopic xenograft mouse model, confirming that CXCL1 was the main mediator of chemotaxis and PDAC growth in this model. These findings shed light on how KDM6A regulates tumor immune microenvironment and PDAC progression and suggest that the CXCL1-CXCR2 axis may be a candidate target for treating PDACs with KDM6A loss.

2022-11-23 | GSE202873 | GEO

TNFα-induced alterations in stromal progenitors in CML BM result in enhanced LSC growth via CXCL1-CXCR2 signaling

Project description:Leukemia stem cells (LSC) are not eradicated in chronic myeloid leukemia (CML) patients responding to tyrosine kinase inhibitor treatment. Bone marrow (BM) mesenchymal niches play an essential role in hematopoietic stem cell (HSC) maintenance. Here, we examined leukemia-induced alterations in mesenchymal progenitor populations using a murine CML model. 6C3+ stroma-forming progenitors were increased in CML BM, and demonstrated enhanced LSC but reduced HSC support compared to their normal counterparts. CML 6C3 cells showed enhanced TNFa-related gene signatures, and upregulated CXCL1 expression. TNFα signaling contributed to expansion and increased CXCL1 expression by 6C3 cells in CML BM. The CXCL1 receptor CXCR2 was upregulated in in LSC, and CXCR2 inhibition significantly reduced LSC growth both in vitro and in vivo. In conclusion, TNFα-induced alterations in stromal progenitors in CML BM result in enhanced CML LSC growth via CXCL1-CXCR2 signaling. Targeting this axis represents a novel therapeutic strategy to inhibit BM niche-protected LSC.

2021-06-16 | GSE126547 | GEO

A Developmentally Prometastatic Niche in Neonatal Liver to Hepatoblastoma mediated by Cxcl1/Cxcr2 Axis

Project description:We find that various HB cell lines including HepG2 cells are consistently and considerably more tumorigenic and metastatic in the P5Tx model than in the P60Tx models. Sc-RNAseq of the P5Tx and P60Tx HepG2 models reveals that the P5Tx tumor is more hypoxic and has more activated hepatic stellate cells (aHSCs) in the tumor-surrounding liver which express significantly higher levels of Cxcl1 than those from the P60Tx model. We find these differences are developmentally present in the normal P5 and P60 liver. We show that Cxcl1/Cxcr2 axis mediates HB cell migration and is critical to HB cell survival under hypoxia. Treating HepG2 P60Tx model with recombinant CXCL1 protein induces multifocal intrahepatic and pulmonary metastasis and CXCR2 knockout in HepG2 cells abolishes their metastatic potential in the P5Tx model. Lastly, we show that in metastatic HB patient tumors there is a similar larger population of aHSCs in the tumor-surrounding liver than the localized tumors, and tumor hypoxia is significantly associated with HB patient prognosis.

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Effect of CXCL1 and CXCL1 with SX-682 on gene expression for human epidermal melanocytes (NHEM) cells.

Project description:To gain insight into how CXCL1 activation of CXCR2 regulates the expression of stemness and differentiation markers, RNAseq analysis was performed on normal human epidermal melanocyte (NHEM) cultures treated with CXCL1 or with CXCL1 and SX-682.

2023-06-07 | GSE223285 | GEO

A Developmentally Prometastatic Niche in Neonatal Liver to Hepatoblastoma mediated by Cxcl1/Cxcr2 Axis

Project description:Hepatoblastoma (HB) is the most common pediatric liver cancer. Its exclusive occurrence in very young children leads us to investigating whether the immature liver provides a protumorigenic niche to HB development. We employed the single-cell RNA-sequencing (sc-RNAseq) to comprehensively profile the HB tumors and their microenvironment in the orthotopic transplantation models established in postnatal day 5 and 60. We demonstrated that the neonatal liver provides a prometastatic niche to HB development via Cxcl1/Cxcr2 axis-mediated HB-aHSC interaction.

2023-01-31 | GSE186027 | GEO

RNA-seq of 32D clone 3 cells transfected with CXCR2 (pEGFP-N1-CXCR2) or an empty vector (pEGFP-N1) with CXCL1/2 treatment

Project description:Purpose: To elucidate a potential role of non-coding RNA in myeloid progenitor cells during the differentiation induced by CXCR2 activation, the 32D clone 3 cells transfected with CXCR2 to simulate GMPs and were examined by RNA sequencing

2020-10-07 | GSE140723 | GEO

A Developmentally Prometastatic Niche in Neonatal Liver to Hepatoblastoma mediated by Cxcl1/Cxcr2 Axis

Project description:A Developmentally Prometastatic Niche in Neonatal Liver to Hepatoblastoma mediated by Cxcl1/Cxcr2 Axis

| PRJNA773415 | ENA

A Developmentally Prometastatic Niche in Neonatal Liver to Hepatoblastoma mediated by Cxcl1/Cxcr2 Axis

Project description:A Developmentally Prometastatic Niche in Neonatal Liver to Hepatoblastoma mediated by Cxcl1/Cxcr2 Axis

| PRJNA772289 | ENA

RNA-seq of 32D clone 3 cells transfected with CXCR2 (pEGFP-N1-CXCR2) or an empty vector (pEGFP-N1) with CXCL1/2 treatment

Project description:RNA-seq of 32D clone 3 cells transfected with CXCR2 (pEGFP-N1-CXCR2) or an empty vector (pEGFP-N1) with CXCL1/2 treatment

| PRJNA590697 | ENA

KDM6A Loss Recruits Tumor-Associated Neutrophils and Promotes Neutrophil Extracellular Trap Formation in Pancreatic Cancer.

Project description:Lysine (K)-specific demethylase 6A (KDM6A) is a frequently mutated tumor suppressor gene in pancreatic ductal adenocarcinoma (PDAC). However, the impact of KDM6A loss on the PDAC tumor immune microenvironment is not known. This study used a genetically engineered, pancreas-specific Kdm6a knockout (KO) PDAC mouse model and human PDAC tissue samples to demonstrate that KDM6A loss correlates with increased tumor-associated neutrophils and neutrophil extracellular traps (NET) formation, which are known to contribute to PDAC progression. Genome-wide bromouridine sequencing analysis to evaluate nascent RNA synthesis showed that the expression of many chemotactic cytokines, especially CXC motif chemokine ligand 1 (CXCL1), was upregulated in KDM6A KO PDAC cells. KDM6A-deficient PDAC cells secreted higher levels of CXCL1 protein, which in turn recruited neutrophils. Furthermore, in a syngeneic orthotopic mouse model, treatment with a CXCL1 neutralizing antibody blocked the chemotactic and NET-promoting properties of KDM6A-deficient PDAC cells and suppressed tumor growth, confirming CXCL1 as a key mediator of chemotaxis and PDAC growth driven by KDM6A loss. These findings shed light on how KDM6A regulates the tumor immune microenvironment and PDAC progression and suggests that the CXCL1-CXCR2 axis may be a candidate target in PDAC with KDM6A loss.SignificanceKDM6A loss in pancreatic cancer cells alters the immune microenvironment by increasing CXCL1 secretion and neutrophil recruitment, providing a rationale for targeting the CXCL1-CXCR2 signaling axis in tumors with low KDM6A.

| S-EPMC9669233 | biostudies-literature

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