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

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

PROVIDER: PRJNA522303 | ENA |

REPOSITORIES: ENA

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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.

2022-04-01 | GSE186335 | GEO

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

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

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

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

Re-education of tumor-associated macrophages by CXCR2 blockade drives senescence and tumor inhibition in advanced prostate cancer

Project description:Tumor-associated macrophages (TAMs) represent a major component of the tumor microenvironment that supports tumorigenesis. Here we found that prostate tumors are strongly infiltrated by TAMs expressing the C-X-C chemokine receptor type 2 (CXCR2). Pharmacological blockade of the CXCR2 receptor by a selective antagonist promoted the re-education of TAMs towards a pro-inflammatory phenotype. Strikingly, CXCR2 knockout monocytes infused in Ptenpc-/-; Trp53pc-/- mice preferentially differentiatied in TNFα-releasing pro-inflammatory macrophages leading to senescence induction and tumor inhibition. Moreover, tumor cells harboring PTEN deletion were more sensitive to TNFα-induced senescence, when compared to PTEN WT tumors, due to increased levels of TNFR1. Our results identify TAMs as a target in prostate cancer therapy and describe a novel therapeutic strategy based on CXCR2 blockade to harness the anti-tumorigenic potential of macrophages against this disease.

2019-12-10 | GSE124058 | GEO

Gene expression profile at single cell level of Lin-Sca-1+c-Kit+ cells (LSKs) from miR-142 WT CML mice (CP LSC) and of LSKs from miR-142 KO CML mice (BC LSC). [scRNA-Seq]

Project description:To assess how the miR-142 deficit affected the BM LSC-enriched LSK landscape, we conducted a single cell RNA-seq analysis of BM miR-142+/+ BCR-ABL (CP CML) and miR-142−/− BCR-ABL (BC CML) LSKs which were harvested from the respective mice, 2 weeks after BCR-ABL induction.

2022-11-02 | GSE217076 | GEO

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