Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Single-cell RNA transcriptome sequencing revealed that androgen/AR signaling promotes neutrophil precursors proliferation in bone marrow

ABSTRACT: The liver is one of the most-favored distant metastatic sites for solid tumors, and interactions between cancer cells and components of the hepatic microenvironment are essential for liver metastasis (LM). Although sex is one of the determinants for primary liver cancer, sexual disparity/dimorphism in LM (SDLM) and the underlying mechanisms remain unclear. We herein demonstrated a significant male-biased SDLM, which was attributed to host androgen/androgen receptor (AR) signaling that promoted hepatic seeding of tumor cells and subsequent outgrowth in a neutrophil-dependent manner. Mechanistically, androgen/AR signaling promoted hepatic accumulation of neutrophils by promoting proliferation and development of neutrophil precursors in the bone marrow, as well as modulating hepatic recruitment of neutrophils and their functions. Antagonizing the androgen/AR/neutrophil axis significantly mitigated LM in males. Our data thus reveal an important role of androgen in LM and suggest that androgen/AR modulation represents a promising target for LM therapy in men.

ORGANISM(S): Mus musculus

PROVIDER: GSE198175 | GEO | 2022/03/12

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Cholestasis-induced neutrophil phenotypic transformation contributes to the immune escape of colorectal liver metastasis

Project description:Cholestasis, a serious complication of liver metastasis (LM), contributes to dismal prognosis in patients with colorectal cancer and LM. However, the mechanism underlying the effect of cholestasis on the development of LM or pre-metastatic microenvironment in the liver remains elusive. In this study, we discovered that cholestasis accelerated the progression of LM and is associated with increased neutrophil infiltration, T-cell exclusion, and exhaustion. Besides, Tβ-MCA and GCA promoted the expression of Arg1 and iNOS in neutrophils via the p38/MAPK signaling pathway. The significant suppression of the activation and cytotoxic effects of CD8+ T cells during co-culture with BA-pretreated neutrophils indicated that BAs directly induce the polarization of immunosuppressive neutrophils. Importantly, targeting BA anabolism with Obeticholic acid effectively suppressed the LM of colorectal cancer in a cholestasis mouse model. Our findings suggest that cholestasis, associated with the failure to achieve drainage of primary BAs, accelerates the progression of LM by remodeling the tumor immune microenvironment. Moreover, targeting BA anabolism with OCA may represent a therapeutic strategy for cholestasis-associated LM of colorectal cancer.

2024-07-10 | GSE209836 | GEO

Male sex affects type I/type II interferon response of neutrophils during hepatic Amebiasis

Project description:Hepatic amebiasis, a serious complication caused by the parasite Entamoeba histolytica, predominantly affects men. Earlier research in the murine disease model indicated that testosterone modulates an intense immune reaction, triggering destructive immunopathological changes in the liver. Inflammatory monocytes expressing proinflammatory chemokines, crucial for neutrophil recruitment, worsen this process. This study examines sex-related variances in neutrophils during hepatic amebiasis in a mouse model. Male subjects exhibited higher levels and recruitment of neutrophils compared to females. Androgens directly contributed to this bias, enhancing neutrophil recruitment and retarding maturation in response to infection. Transcriptomic analysis revealed diminished type I and II interferon-stimulated gene expression and reduced activation pathways in male neutrophils versus female neutrophils. Upon ex-vivo stimulation, female human neutrophils showed higher expression of a key type I interferon-stimulated gene (viperin/RSAD2) at the protein level, which was similar in mice after infection, and suppressed by testosterone. In male mice with hepatic amebiasis, sex-dependent factors led to recruitment of less active neutrophils, intensifying immunopathological damage to liver tissue. This sex disparity and testosterone's impact on interferon-stimulated genes hold implications beyond hepatic amebiasis, potentially influencing broader areas, including viral infectious diseases

2024-01-10 | GSE242045 | GEO

A neutrophil - B-cell axis impacts tissue damage control during sepsis via Cxcr4

Project description:Sepsis is a life-threatening condition characterized by uncontrolled systemic inflammation and coagulation, leading to multi-organ failure. Therapeutic options to prevent sepsis-associated immunopathology remain scarce. Here, we established a mouse model of long-lasting disease tolerance during severe sepsis, manifested by diminished immunothrombosis and organ damage in spite of a high pathogen burden. We found that, both neutrophils and B cells emerged as key regulators of tissue integrity. Enduring changes in the transcriptional profile of neutrophils, included upregulated Cxcr4 expression in protected, tolerant hosts. Neutrophil Cxcr4 upregulation required the presence of B cells, suggesting that B cells promoted disease tolerance by improving tissue damage control via the suppression of neutrophils’ tissue damaging properties. Finally, therapeutic administration of a Cxcr4 agonist successfully promoted tissue damage control and prevented liver damage during sepsis. Our findings highlight the importance of a critical B-cell/neutrophil interaction during sepsis and establish neutrophil Cxcr4 activation as a potential means to promote disease tolerance during sepsis.

2022-08-04 | GSE210207 | GEO

Characterization and Function of Neutrophils in Alcoholic Hepatitis in Humans and Mice: Roles for Neutrophilic p47phox in Disease Progression

Project description:Intrahepatic neutrophil infiltration has been implicated in the pathogenesis of severe alcoholic hepatitis (SAH), a disease with high short-term morality; however, how neutrophils contribute to SAH progression remain obscure. This study aimed to characterize intrahepatic neutrophil infiltration and its involvement in AH pathogenesis. We found that hepatic expression of neutrophil cytosolic factor 1 (NCF1), a key factor in controlling neutrophilic ROS production, was upregulated and correlated with neutrophil number, inflammation and ROS-associated genes in SAH patients. Ncf1 floxed mice were generated using CRISPR/Cas9 technology by inserting two LoxP sequences into intron 1 and intron 8 of the mouse Ncf1 gene, then crossed with Lyz Cre mice to generated myeloid cell-specific Ncf1 knockout (Ncf1Lyz-/-) mice. The LyzCre negative Ncf1 floxed mice were used as corresponding WT littermate control. The chronic-plus-binge ethanol feeding model was used in this study. The total RNAs were extracted from ETOH-fed 5 WT and 4 Ncf1Lyz-/- mouse livers and submitted for a Poly(A) RNA sequencing. Genetic deletion of the Ncf1 gene in neutrophils abolished hepatic ROS, inflammation, and fibrosis induced by ethanol feeding. RNA-sequencing analysis and the data from experimental models revealed that neutrophilic NCF1-dependent ROS promoted alcoholic liver injury by inhibiting AMP-activated protein kinase (a key regulator of lipid metabolism) and microRNA-223 (a key anti-inflammatory and anti-fibrotic microRNA). Our data suggest that divergent pathogeneses exist in SAH and neutrophilic NCF1-dependent ROS promotes alcoholic liver injury by inhibiting AMPK and microRNA-223.

2022-07-16 | GSE192720 | GEO

Selective androgen receptor degrader (SARD) to overcome antiandrogen resistance in castration-resistant prostate cancer

Project description:Clinical resistance such as androgen receptor (AR) mutation, AR overexpression, and AR splice variants (ARVs) restrict the second-generation antiandrogens benefit in patients with castration-resistant prostate cancer (CRPC). Several strategies have been implemented to develop novel antiandrogens to circumvent the occurring resistance. In this study, based on rational drug design, we discovered and identified a bifunctional small molecule Z15 as a potent AR antagonist and AR selective degrader. Z15 could directly bind to the AR ligand-binding domain (LBD) and inhibited DHT-induced AR nuclear translocation. Furthermore, Z15 promoted AR degradation through the proteasome pathway. As a result, our in vitro and in vivo studies showed Z15 efficiently suppressed AR and AR mutant transcription activity, downregulated mRNA and protein levels of AR target genes, as well as overcame AR LBD mutations, AR amplification, and ARVs-induced resistance in CRPC. In conclusion, our data illustrate the synergistic importance of AR antagonism and degradation in advanced prostate cancer treatment.

2023-02-02 | PXD035721 | Pride

An androgen signaling axis uses a writer and a reader of ADP-ribosylation to control protein complex assembly

Project description:Androgen signaling through the androgen receptor (AR) regulates multiple pathways in both normal and prostate cancer cells. Androgen regulates diverse aspects of the AR life cycle, including its post-translational modification, but understanding how specific modifications influence AR activity has been mostly elusive. Here, we show that androgen regulates AR through a pathway mediated by the mono-ADP ribosyltransferase, Parp7. We show that Parp7 ADP-ribosylates AR on multiple cysteines, and that a subset of these sites mediates agonist-specific recruitment of the E3 ligase Dtx3L/Parp9. Tandem macrodomains in Parp9 selectively recognize ADP ribosylated AR, and Dtx3L/Parp9 affects expression of a subset of AR-regulated genes. Parp7, ADP-ribosylation of AR, and AR-Dtx3L/Parp9 complex assembly are inhibited by 60 Olaparib, a compound used clinically to inhibit poly-ADP-ribosyltransferases Parp1/2. Our study reveals the components of a new androgen signaling axis that uses a writer and reader of ADP-ribosylation to modulate AR activity.

2021-05-28 | PXD018811 | Pride

An androgen signaling axis uses a writer and a reader of ADP-ribosylation to control protein complex assembly

2021-04-23 | PXD025195 | Pride

Immature low-density neutrophils exhibit metabolic flexibility that facilitates breast cancer liver metastasis

Project description:Neutrophils play a key role in the control of metastatic progression. Neutrophils are phenotypically heterogeneous and can exert either anti- or pro-metastatic functions. Here, we demonstrate that tumor cells capable of forming liver metastases induce an accumulation of neutrophils in the peripheral blood and liver parenchyma. Cancer cell-derived G-CSF, in concert with other factors, mobilizes immature low-density neutrophils that promote liver metastasis. In contrast, mature high-density neutrophils inhibit the formation of liver metastases. Transcriptomic and metabolomic analyses of high- and low- density neutrophils reveal engagement of numerous metabolic pathways specifically in low-density neutrophils. Low-density neutrophils exhibit enhanced global bioenergetic capacity, through their ability to engage mitochondrial-dependent ATP production, and remain capable of executing pro-metastatic neutrophil functions, including NETosis, under nutrient-deprived conditions. Together, these data reveal that distinct pro-metastatic neutrophil populations exhibit a high degree of metabolic flexibility, which facilitates metastatic progression and the formation of liver metastases.

2019-06-26 | GSE123669 | GEO

Hes6 expression is controlled by c-Myc and the AR to promote E2F1 activity and poor outcome in castrate-resistant prostate cancer (xenografts)

Project description:Hes6 is a transcription co-factor that is associated with stem cell characteristics in neural tissue, but its role in cancer remains uncertain. Here we show that Hes6 is controlled by c-Myc and the AR and can drive castration resistance in xenografts of the androgen-dependent LNCaP prostate cancer cell line model. Hes6 activates a cell cycle enhancing transcriptional network that maintains tumour growth in the absence of circulating androgen but with maintained nuclear AR. We demonstrate interaction between E2F1, the AR and Hes6 and show the co-dependency of these factors in the castration-resistant setting. In the clinical setting, we have discovered a Hes6-associated signature that predicts poor outcome in prostate cancer, which could be pharmacologically targeted. LNCaP-LM (luciferase expressing) cells with stable Hes6-overexpression and empty vector controls injected dorso-subcutaneously into NOD SCID gamma (NSG) mice. Mice were castrated when average graft size reached 100mm3 . Mice were culled after 12 weeks growth and grafts harvested.

2014-04-17 | E-GEOD-36433 | biostudies-arrayexpress

Spermine is a natural suppressor of AR signaling in castration-resistant prostate cancer

Project description:In castration-resistant prostate cancer (CRPC), clinical response to androgen receptor (AR) antagonists is limited mainly due to AR-variants expression and restored AR signaling. The metabolite spermine is most abundant in prostate and it decreases as prostate cancer progresses, but its functions remain poorly understood. Here, we show spermine inhibits full-length androgen receptor (AR-FL) and androgen receptor splice variant 7 (AR-V7) signaling and suppresses CRPC cell proliferation by directly binding and inhibiting protein arginine methyltransferase PRMT1. Spermine reduces H4R3me2a modification at the AR locus and suppresses AR binding as well as H3K27ac modification levels at AR target genes. Spermine supplementation restrains CRPC growth in vivo. PRMT1 inhibition also suppresses AR-FL and AR-V7 signaling and reduces CRPC growth. Collectively, we demonstrate spermine as an anticancer metabolite by inhibiting PRMT1 to transcriptionally inhibit AR-FL and AR-V7 signaling in CRPC, and we indicate spermine and PRMT1 inhibition as powerful strategies overcoming limitations of current AR-based therapies in CRPC.

2023-10-11 | MTBLS8034 | MetaboLights

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

Tweets

OmicsDI Databases

PRIDE
PeptideAtlas
MassIVE
JPOST Repository
Physiome Model Repository

EGA
EVA
ENA
LINCS
PAXDB
Cell Collective

MetaboLights
Metabolomics Workbench
MetabolomeExpress
GNPS
BioModels
FAIRDOMHub

ArrayExpress
dbGaP
ExpressionAtlas
GEO
NODE

Information

Databases
Help
API
Contact us
Code on GitHub
Terms of use
Submit Data