Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Pancreatic ductal adenocarcinoma tumor growth requires SREBP pathway activity

ABSTRACT: Tumor growth outstrips local nutrient supply, making metabolic reprogramming a necessary component of oncogenesis and cancer progression. The supply of lipids such as cholesterol and fatty acids is required for continued tumor cell division. Sterol regulatory element-binding protein (SREBP) transcription factors control cellular lipid homeostasis by activating genes required for cholesterol and fatty acid synthesis and uptake. SREBPs have been implicated in the progression of multiple cancers, including glioblastoma, breast, colon, liver and prostate. However, the role the SREBP pathway and its central regulator SREBP cleavage activating protein (SCAP) in pancreatic ductal adenocarcinoma (PDAC) has not been studied in detail. Here, we demonstrate that SREBP target genes are upregulated in PDAC tumors, and SREBPs are upregulated in patient-derived PDAC cell lines under low serum conditions that mimic the tumor microenvironment. Chemical or genetic inhibition of the SREBP pathway prevented PDAC cell growth under low serum conditions due to a lack of lipid supply. Using subcutaneous and orthotopic xenograft models, we showed that SCAP is required for PDAC tumor growth. Pancreas-specific knockout of Scap had no effect on mouse pancreas development or function, allowing examination of the role for Scap in the murine KPC model of PDAC. Notably, heterozygous loss of Scap significantly prolonged survival in KPC mice, and homozygous loss of Scap impaired PDAC tumor inception. Collectively, these results demonstrate that SCAP and SREBP pathway activity are essential for PDAC cell and tumor growth in vitro and in vivo, identifying SCAP as a potential therapeutic target for PDAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235100 | GEO | 2024/10/09

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Deletion of Scap in Alveolar Type II Cells Influences Lung Lipid Homeostasis and Identifies a Compensatory Role for Pulmonary Lipofibroblasts

Project description:Pulmonary function after birth is dependent upon surfactant lipids that reduce surface tension in the alveoli. The sterol-responsive element-binding proteins (SREBPs) are transcription factors regulating expression of genes controlling lipid homeostasis in many tissues. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (Scap∆/∆) in vivo. Prior to birth (E18.5), deletion of Scap decreased the expression of both SREBPs and a number of genes regulating fatty acid and cholesterol metabolism. Nevertheless, Scap∆/∆ mice survived postnatally, surfactant and lung tissue lipids being substantially normalized in adult Scap∆/∆ mice. Although phospholipid synthesis was decreased in type II cells from adult Scap∆/∆ mice, lipid storage, synthesis, and transfer by lung lipofibroblasts were increased. mRNA microarray data indicated that SCAP influenced two major gene networks, one regulating lipid metabolism and the other stress-related responses. Deletion of the SCAP/SREBP pathway in respiratory epithelial cells altered lung lipid homeostasis and induced compensatory lipid accumulation and synthesis in lung lipofibroblasts. To identify the role of SREBPs in the lung, we conditionally deleted the SREBP cleavage-activating protein gene, Scap, in respiratory epithelial cells (Scap∆/∆) in vivo.Lung cRNA was hybridized to the murine genome MOE430 V2 chips.

2011-01-08 | E-GEOD-26496 | biostudies-arrayexpress

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [MG_U74Cv2]

Project description:The synthesis of fatty acids and cholesterol is regulated by three membrane-bound transcription factors: sterol regulatory element-binding proteins (SREBP)-1a, -1c, and -2. Their function in liver has been characterized in transgenic mice that overexpress each SREBP isoform and in mice that lack all three nuclear SREBPs because of gene knockout of SREBP cleavage-activating protein (SCAP) required for nuclear localization of SREBPs. Here, we use oligonucleotide arrays hybridized with RNA from livers of three lines of mice (transgenic for SREBP-1a, transgenic for SREBP-2, and knockout for SCAP) to identify genes that are likely to be direct targets of SREBPs in liver. Application of stringent combinatorial criteria to the transgenic/knockout approach allows identification of genes whose activities are likely controlled directly by the SREBPs.

2017-08-05 | GSE102258 | GEO

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [MG_U74Bv2]

2017-08-05 | GSE102257 | GEO

Combined analysis of oligonucleotide microarray data from transgenic and knockout mice identifies direct SREBP target genes [MG_U74Av2]

2017-08-05 | GSE102256 | GEO

Deletion of Scap in Alveolar Type II Cells Influences Lung Lipid Homeostasis and Identifies a Compensatory Role for Pulmonary Lipofibroblasts

2011-01-08 | GSE26496 | GEO

Liver tumor gene expression profile of liver-specific PTEN KO, PTEN/SCAP double KO mice

Project description:Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is characterized by hepatic steatosis and hepatocellular injury and progresss cirrhosis and hepatocellular carcinoma. Sterol regulatory elment-binding proteins (SREBPs) are master regulators of lipogenesis. Liver-specific PTEN knockout (KO) mice show constitutive upregulation of SREBP through PI3K-Akt pathway activation, leading to spontaneous fatty liver and subsequent HCC development. SREBP cleavage-activating protein (SCAP) plays a critical role in SREBP activation. We sought to determine the impact of SREBP inhibition on NASH and HCC development. To this end, we additionaly inhibited SREBP pathway in liver-specific PTEN mice by ablating SCAP and generated liver-specific PTEN/SCAP double KO (DKO) mice. However unexpectedly, inhibition of SCAP/SREBP pathway markedly exacerbated liver injury (5weeks), fibrosis (5months), and carcinogenesis (7 months) in PTEN KO mice. To elucidate the mechanisms of liver tumorigenesis in liver-specific PTEN/SCAP DKO mice, we conducted transcriptome analyses of the livers.

2022-04-05 | GSE174173 | GEO

Liver gene expression profile of wild type, liver-specific PTEN KO, SCAP KO and PTEN/SCAP double KO mice.

Project description:Nonalcoholic steatohepatitis (NASH), a severe form of nonalcoholic fatty liver disease, is characterized by hepatic steatosis and hepatocellular injury and progresses to cirrhosis and hepatocellular carcinoma. Sterol regulatory element-binding proteins (SREBPs) are master regulators of lipogenesis. Liver-specific PTEN knockout (KO) mice show constitutive upregulation of SREBP through PI3K-Akt pathway activation, leading to spontaneous fatty liver and subsequent HCC development. SREBP cleavage-activating protein (SCAP) plays a critical role in SREBP activation. We sought to determine the impact of SREBP inhibition on NASH and HCC development. To this end, we additionally inhibited SREBP pathway in liver-specific PTEN mice by ablating SCAP and generated liver-specific PTEN/SCAP double KO (DKO) mice. However unexpectedly, inhibition of SCAP/SREBP pathway markedly exacerbated liver injury (5weeks), fibrosis (5months), and carcinogenesis (7 months) in PTEN KO mice. To elucidate the mechanisms of liver injury in liver-specific PTEN/SCAP DKO mice, we conducted transcriptome analyses of the livers.

2022-04-05 | GSE169104 | GEO

A suite of haploid genetic screens identifies SPRING as a novel determinant of SREBP signaling and cholesterol metabolism

Project description:The sterol-regulatory element binding protein (SREBP) transcription factors are central transcriptional regulators of sterol- and fatty acid metabolism. Using a suite of human haploid genetic screens, we identify the SREBP Regulating Gene (SPRING; C12ORF49) as a novel regulator of this pathway. SPRING is a glycosylated Golgi-resident membrane protein. Genetic ablation of SPRING in human Hap1 cells, murine Hepa1-6 hepatoma cells, and in primary murine hepatocytes leads to a marked reduction in SREBP signaling. In mice, deletion of Spring results in embryonic lethality. However, we show that adenoviral-mediated silencing of hepatic Spring expression also attenuates the SREBP response. Mechanistically, we demonstrate that attenuated SREBP signaling in SPRINGKO cells is a result of reduced SREBP cleavage-activating protein (SCAP) and its mislocalization. Whereas in control cells SCAP cycles between the ER and the Golgi in a sterol-dependent manner, in SPRINGKO cells SCAP is trapped in the Golgi irrespective of the cellular sterol status. Consistent with limited functional SCAP in SPRINGKO cells, reintroducing SCAP restores SREBP-dependent signaling, cholesterol biosynthesis, and lipoprotein uptake. Consistent with SREBP signaling being required for cell growth and proliferation, a wide range of human tumor cell lines display dependency on SPRING expression. In conclusion, we identify SPRING as a previously unrecognized determinant of the SREBP pathway that is essential for proper SCAP function.

2020-01-23 | GSE143530 | GEO

HSPA8 dampens SCAP/INSIG split and SREBP activation by reducing PKR-mediated INSIG phosphorylation

Project description:Lipid accumulation in the renal tubules is a major determinant of diabetic kidney disease (DKD), and activation of SREBPs plays a central role in this process. Our study aimed to explore whether HSPA8, a molecular chaperone, is the master regulator of INSIG/SREBPs function in DKD. Here, we showed that tubular epithelial cell (TEC)-specific knockout of HSPA8 upregulated the phosphorylation of INSIG1 and INSIG2, which disrupted the interaction between INSIG proteins and SCAP, leading to the translocation of the SCAP-SREBP complex to the Golgi apparatus, and the activation of SREBPs. TEC-specific overexpression of HSPA8 restrained these changes. INSIG1 and INSIG2 can be phosphorylated by protein kinase R (PKR), while HSPA8 can recognize PKR and recruit the E3 ubiquitin ligase (CHIP) to promote PKR ubiquitination and degradation. SREBP1 transcriptionally activated HSPA8 expression under temporary hyperglycemic stimulation. However, persistent hyperglycemia reduced HSPA8 levels by promoting nuclear factor (NF)-κB-mediated transcriptional inhibition and reducing USP43-mediated deubiquitination of HSPA8. Collectively, these findings indicate that the molecular chaperone HSPA8 serves as a negative feedback regulator of SREBPs, lipogenesis, and DKD development.

2024-12-12 | GSE283754 | GEO

Microbiome-dependent tryptophan metabolism suppresses inflammatory immunity in the pancreatic tumor microenvironment by activation of the aryl hydrocarbon receptor [RNA-seq]

Project description:To explore the role of macrophages and AhR in PDAC, we used an orthotopic model employing mouse PDAC organoid lines derived from a primary tumor isolated from the KPC model of PDAC and performed RNA-sequencing on FACS-sorted TAM from 14-day tumors and compared them to the residential macrophages from normal pancreas.

2022-03-31 | GSE171601 | 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