Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Effects of deletion of SAT1, a polyamine-metabolic enzyme, on mouse HeLa xenograft tumor

ABSTRACT: An acidic tumor microenvironment plays a critical role in tumor progression. However, understanding of metabolic reprogramming of tumors in response to acidic extracellular pH has remained elusive. Using comprehensive metabolomic analyses, we demonstrated that acidic extracellular pH (pH 6.8) leads to the accumulation of N1-acetylspermidine, a pro-tumor metabolite, through upregulation of the expression of spermidine/spermine acetyl transferase 1 (SAT1). Inhibition of SAT1 expression suppressed the accumulation of intra- and extracellular N1-acetylspermidine at acidic pH. Conversely, overexpression 3 of SAT1 increased intra- and extracellular N1-acetylspermidine levels, supporting the proposal that SAT1 is responsible for accumulation of N1-acetylspermidine. While inhibition of SAT1 expression only had a minor effect on cancer cell growth in vitro, SAT1 knockdown significantly decreased tumor growth in vivo, supporting a contribution of the SAT1-N1-acetylspermidine axis to pro-tumor immunity. Immune cell profiling revealed that inhibition of SAT1 expression decreased neutrophil recruitment to the tumor, resulting in impaired angiogenesis and tumor growth. We showed that anti-neutrophil neutralizing antibodies suppressed growth in control tumors to a similar extent to that seen in SAT1 knockdown tumors in vivo. Further, a SAT1 signature was found to be correlated with poor patient prognosis. Our findings demonstrate that extracellular acidity stimulates recruitment of pro-tumor neutrophils via the SAT1-N1-acetylspermidine axis, which may represent a novel target for anti-tumor immune therapy.

ORGANISM(S): Homo sapiens

PROVIDER: GSE239784 | GEO | 2023/08/14

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Gene expression in PANC-1 and AsPC-1 human pancreatic carcinoma cells under hypoxia, nutrient starvation and low pH culture condition.

Project description:The conditions of the tumor microenvironment, such as hypoxia and nutrient starvation, play critical roles in cancer progression. However, the role of acidic extracellular pH in cancer progression is not studied as extensively as that of hypoxia. Here, we show that extracellular acidic pH (pH 6.8) triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nuclear translocation and promoter binding to its targets along with intracellular acidification. Interestingly, inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterol biosynthesis-related genes. Moreover, acyl-CoA synthetase short-chain family member 2 (ACSS2), a direct SREBP2 target, provided a growth advantage to cancer cells under acidic pH. Furthermore, acidic pH-responsive SREBP2 target genes were associated with reduced overall survival of cancer patients. Thus, our findings show that SREBP2 is a key transcriptional regulator of metabolic genes and progression of cancer cells, partly in response to extracellular acidification.

2017-01-25 | GSE93988 | GEO

Open chromatin region, histone acetylation, and SREBP2 binding in PANC-1 and AsPC-1 human pancreatic carcinoma cells under hypoxia, nutrient starvation and low pH culture condition.

2017-01-25 | GSE93982 | GEO

microarray analysis in SREBP2-knockdown cells under low pH (pH 6,8) culture conditions

2017-01-25 | GSE93980 | GEO

Microarray analysis of T-cell death-associated gene 8 (TDAG8)-mediated gene expression in mouse Lewis lung carcinoma (LLC) cells.

2012-11-01 | GSE31776 | GEO

Microarray analysis of T-cell death-associated gene 8 (TDAG8)-mediated gene expression in mouse Lewis lung carcinoma (LLC) cells.

Project description:We previously identified an extracellular pH-sensing G protein-coupled receptor T cell death associated gene 8 (TDAG8) as an extracellular pH sensor of tumor cells that promotes cell growth/survival in vitro and tumor development in vivo. To determine genes regulated by TDAG8 in vitro, mouse Lewis lung carcinoma (LLC) cells stably expressing TDAG8 (TDAG8-LLC cells) and control vector (control LLC cells) were cultured under acidic conditions. Transcriptome microarray analysis using Affymetrix GeneChip Mouse Genome 430 2.0 Arrays was performed with total RNA prepared from these cells. To determine genes regulated by TDAG8 in vitro, mouse Lewis lung carcinoma (LLC) cells stably expressing TDAG8 (TDAG8-LLC cells) and control vector (control LLC cells) were cultured under acidic conditions. Transcriptome microarray analysis using Affymetrix GeneChip Mouse Genome 430 2.0 Arrays was performed with a mixture of equal amounts of total RNA samples from four independent cell cultures.

2012-11-01 | E-GEOD-31776 | biostudies-arrayexpress

Stephanou2019 - pH as a potential therapeutic target to improve temozolomide antitumor efficacy

Project description:Abstract: Despite intensive treatments including temozolomide (TMZ) administration, glioblastoma patient prognosis remains dismal and innovative therapeutic strategies are urgently needed. A systems pharmacology approach was undertaken to investigate TMZ pharmacokinetics‐pharmacodynamics (PK‐PD) incorporating the effect of local pH, tumor spatial configuration and micro‐environment. A hybrid mathematical framework was designed coupling ordinary differential equations describing the intracellular reactions, with a spatial cellular automaton to individualize the cells. A differential drug impact on tumor and healthy cells at constant extracellular pH was computationally demonstrated as TMZ‐induced DNA damage was larger in tumor cells as compared to normal cells due to less acidic intracellular pH in cancer cells. Optimality of TMZ efficacy defined as maximum difference between damage in tumor and healthy cells was reached for extracellular pH between 6.8 and 7.5. Next, TMZ PK‐PD in a solid tumor was demonstrated to highly depend on its spatial configuration as spread cancer cells or fragmented tumors presented higher TMZ‐induced damage as compared to compact tumor spheroid. Simulations highlighted that smaller tumors were less acidic than bigger ones allowing for faster TMZ activation and their closer distance to blood capillaries allowed for better drug penetration. For model parameters corresponding to U87 glioma cells, inter‐cell variability in TMZ uptake play no role regarding the mean drug‐induced damage in the whole cell population whereas this quantity was increased by inter‐cell variability in TMZ efflux which was thus a disadvantage in terms of drug resistance. Overall, this study revealed pH as a new potential target to significantly improve TMZ antitumor efficacy. Change the value of pH for different cases.

2019-09-30 | MODEL1909300003 | BioModels

Effect of detachment culture condition and depletion of SAT1 on gene expression in SKOV3 ovarian cancer cell line

Project description:Ovarian cancer is an aggressive malignancy characterized by the ascitic fluid and peritoneal metastases. Cancer cells detach from the extracellular matrix and survives the loss of anchorage in the ascites to disseminate extensively in the peritoneal cavity. Metabolic reprogramming is often observed in the cancer progression, yet its role in peritoneal metastasis is largely unexplored. Here we report that spermidine/spermine N1-acetyltransferase 1 (SAT1) promotes the anchorage-independent cell survival and potentiates metastatic dissemination. We compared the detached vs attached cells with RNAseq and identified that hypoxia was among the most enriched pathways using gene set enrichment analysis.To define the underlying mechanism, we first carried out RNA-seq analysis of the detached ovarian cancer cells with or without knocking down SAT1 and identified 1,829 differentially expressed genes (P value < 0.05) in the detached SAT1 knocking down cells. Gene Ontology (GO) term enrichment analysis recognized the differentially expressed genes associated extensively with mitotic process, most likely reflecting a role of SAT1 in cell cycle control. Taken together, our data suggest that SAT1 was induced by hypoxia in the detached cell and played an important role in cell cycle control.

2024-07-29 | GSE267614 | GEO

Identification of acidic extracellular pH-modulated genes

Project description:To investigate the genes that are modulated by acidic extracellular pH, we treated the mouse B16-BL6 cells with acidic medium and then analyzed them comprehensively by cDNA microarray.

2024-09-09 | GSE276124 | GEO

Tumor-associated neutrophils display a distinct N1 profile following TGFβ modulation: A transcriptomics analysis of pro- vs. antitumor TANs

Project description:It is becoming increasingly clear that tumor-associated neutrophils (TANs) play an important role in cancer biology, through direct impact on tumor growth and by recruitment of other cells types into the tumor. The function of neutrophils in cancer has been the subject of seemingly contradicting reports, pointing toward a dual role played by TANs in tumor progression. The existence of multiple neutrophil subsets, as well as phenotypic modulation of the neutrophils by various factors in the tumor microenvironment, has been shown. TGFβ plays a significant role in the determination of neutrophils' phenotype, by shifting the balance from an antitumor (N1) toward a more permissive (N2) phenotype. The full range of mechanisms responsible for the pro- vs. antitumor effects of TANs has not yet been elucidated. Therefore, the ability to identify the different neutrophil subpopulations in the tumor is critical in order to understand TANs evolution and contribution throughout tumor progression. Using a transcriptomic approach, we identified alternations in gene expression profile following TGFβ inhibition. We show that N1 and N2 TANs represent distinct subpopulations with different transcriptional signatures and both differ from naive bone marrow neutrophils. The analysis highlights a clear difference in pathways involved in neutrophil function such as cytoskeletal organization and antigen presentation, as well as alterations in chemokine profile, eventually affecting their effect on tumor cells and tumor growth. These data highlights several potential new pathways and mechanisms by which neutrophils can influence both the tumor cells and the adaptive immune system.

2017-07-19 | GSE101584 | GEO

IL-2 is inactivated by the acidic pH environment of tumors enabling engineering of a pH-selective mutein (scRNA-Seq)

Project description:Cytokines interact with their receptors in the extracellular space to control immune responses. How the physicochemical properties of the extracellular space influence cytokine signaling is incompletely elucidated. Here, we show that the activity of interleukin (IL)-2, a critical cytokine in T cell immunity, is profoundly affected by pH, limiting IL-2 signaling within the acidic environment of tumors. Generation of lactic acid by tumors limits STAT5 activation, effector differentiation and anti-tumor immunity by CD8+ T cells and renders high-dose IL-2 therapy poorly effective. Directed evolution enabled selection of a pH-selective IL-2 mutein (Switch-2). Switch-2 binds the IL-2 receptor subunit IL-2Ra with higher affinity, triggers STAT5 activation and drives CD8+ T cell effector function more potently at acidic pH than at neutral pH. Consequently, high-dose Switch-2 therapy induces potent immune activation and tumor rejection with reduced on-target toxicity in normal tissues. Finally, we find that sensitivity to pH is a generalizable property of a diverse range of cytokines with broad relevance to immunity and immunotherapy in healthy and diseased tissues.

2022-12-02 | GSE213440 | GEO

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