Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy

ABSTRACT: The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) has been attributed to intrinsic resistance to chemotherapy and a growth-permissive tumor microenvironment. Quiescent pancreatic stellate cells (PSCs) are neuroendocrine, nestin-positive, lipid-accumulating cells whose homologues in the liver are the principal repository of Vitamin A esters. Upon activation, lipid droplets are lost and via transdifferentiation they become the key cell type responsible for driving the severe desmoplasia that characterizes PDA. Despite their critical role in PDA progression and chemoresistance, therapeutic strategies targeting PSCs are lacking. Here we identified the vitamin D receptor (VDR) as a master genomic regulator of PSC activation and function. In vitro we demonstrate that VDR activation reduces expression in PSCs of genes implicated in activation, inflammation, and extracellular matrix production, as well as restoring lipid droplet integrity. In vivo, the VDR ligand calcipotriol enhances the anti-tumor effects of gemcitabine by increasing intratumoral concentration 5-fold, reducing tumor volume to near baseline and lowering metastases by more than 65%. These findings implicate VDR as a master regulator of PSC activation and identify a novel therapeutic approach for the treatment of pancreatic cancer.

ORGANISM(S): Mus musculus Homo sapiens

PROVIDER: GSE43770 | GEO | 2014/10/03

SECONDARY ACCESSION(S): PRJNA187388

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Vitamin d receptor-mediated stromal reprogramming suppresses pancreatitis and enhances pancreatic cancer therapy

Project description:The poor clinical outcome in pancreatic ductal adenocarcinoma (PDA) has been attributed to intrinsic resistance to chemotherapy and a growth-permissive tumor microenvironment. Quiescent pancreatic stellate cells (PSCs) are neuroendocrine, nestin-positive, lipid-accumulating cells whose homologues in the liver are the principal repository of Vitamin A esters. Upon activation, lipid droplets are lost and via transdifferentiation they become the key cell type responsible for driving the severe desmoplasia that characterizes PDA. Despite their critical role in PDA progression and chemoresistance, therapeutic strategies targeting PSCs are lacking. Here we identified the vitamin D receptor (VDR) as a master genomic regulator of PSC activation and function. In vitro we demonstrate that VDR activation reduces expression in PSCs of genes implicated in activation, inflammation, and extracellular matrix production, as well as restoring lipid droplet integrity. In vivo, the VDR ligand calcipotriol enhances the anti-tumor effects of gemcitabine by increasing intratumoral concentration 5-fold, reducing tumor volume to near baseline and lowering metastases by more than 65%. These findings implicate VDR as a master regulator of PSC activation and identify a novel therapeutic approach for the treatment of pancreatic cancer. RNA-Seq analyses was used to characterize cancer-associated changes between pre-activated (3-day culture) and activated (7-day culture) primary mouse PSCs, as well as control and PDA human PSCs. RNA-Seq was also used to assess the impact of VDR activation (DMSO vs calcipotriol) in a human PSC line (MiaPaCa-2), the mouse primary PSCs

2014-10-03 | E-GEOD-43770 | biostudies-arrayexpress

A master cistromic circuit governing hepatic fibrogenesis [ChIP-seq]

Project description:Liver fibrosis is a reversible wound-healing response to liver injury and hepatic stellate cells (HSCs) are central cellular players that mediate hepatic fibrogenesis. However, the molecular mechanisms that govern this process remain unclear. Here, we reveal a novel cistromic circuit in HSCs comprising the vitamin D receptor (VDR) and SMAD transcription factors that restrains the intensity of hepatic fibrogenesis. Ligand-activated VDR suppresses TGFβ1-induced pro-fibrotic gene expression in HSCs. Administration of a vitamin D analogue, calcipotriol, diminishes the fibrotic response in a mouse model of liver fibrosis, while VDR knockout mice spontaneous develop extensive hepatic fibrosis by age 6 months. Using ChIP-Seq, we find that the anti-fibrotic properties of VDR are due to crosstalk with SMAD, mediated by their co-occupancy of DNA-binding sites on pro-fibrotic genes. Specifically, SMAD binding potentiates local chromatin accessibility to enhance VDR recruitment at the same cis-regulatory elements, which reciprocally antagonizes the interaction between SMAD3 and chromatin and limits the assembly of transcriptional activation complexes at fibrotic genes, a process that is enhanced by the presence of VDR agonists. These results not only establish this coordinated VDR/SMAD cistromic circuit as a master regulator of hepatic fibrogenesis, but also support VDR as a potential drug target to ameliorate liver fibrosis. Identification of VDR, SMAD3 and H3 binding sites in human stellate LX2 cells that were pre-treated with calcipotriol (100nM) for 16 hrs (where calcipotriol treatment is indicated) followed by incubation of calcipotriol (100nM) or TGFβ1 (1ng/ml) for another 4 hours (where indicated).

2013-04-29 | E-GEOD-38103 | biostudies-arrayexpress

Differential effects of Am80 and calcipotriol administration on gene expression in CAFs

Project description:We investigated how Am80 differed from vitamin D analogues in terms of effects on gene expression in PDAC CAFs. we stimulated primary cultured PSCs isolated from three patients with PDAC (PSC163, PSC52, and PSC119) with dimethyl sulfoxide (DMSO, control), Am80, or calcipotriol. Gene expression profiles were then compared using microarray-based transcriptomic analysis. Extracting genes that were differentially expressed between Am80- and calcipotriol-treated cells revealed that Meflin expression was more significantly upregulated by Am80 than calcipotriol. Interestingly, the expression levels of fibroblast activation protein (FAP) and chemokine (C-C motif) ligand 2 (CCL2), which are markers of pCAFs, were higher in Am80-treated PSCs than calcipotriol-treated PSCs, whereas the expression levels of other pCAF marker genes, such as C-X-C motif chemokine ligand 12 (CXCL12), podoplanin (PDPN) and periostin (POSTN), were higher in calcipotriol-treated cells. These data suggested that Am80 and calcipotriol differentially regulated gene expression in PSCs.

2021-07-03 | GSE179318 | GEO

A master cistromic circuit governing hepatic fibrogenesis [ChIP-seq]

2013-04-29 | GSE38103 | GEO

Effect of Calcipotriol on gene expression in gastrocnemius muscle of SKO mice.

Project description:Further investigation is needed to understand the role of vitamin D in muscle function. In this study, we utilized SOD1 gene knockout mice as a model of muscular atrophy and intervened with the VDR ligand calcipotriol to observe its effects on muscle function. RNAseq analysis was employed to examine the impact of calcipotriol on gene expression in the gastrocnemius muscle, aiming to elucidate its underlying mechanisms. The results revealed that calcipotriol primarily exerted its effects through pathways related to protein synthesis and mitochondrial function.

2024-12-01 | GSE249868 | GEO

ERAP2 is a novel target involved in autophagy and activation of pancreatic stellate cells via unfolded protein response signaling pathway

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by excessive desmoplasia and autophagy-dependent tumorigenic growth. Pancreatic stellate cells (PSCs) as a predominant stromal cell type play a critical role in PDAC biology. Autophagy facilitates PSC activation. However, the mechanism remains unknown. To investigate the mechanism of autophagy in PSC activation, gene expression profiles between patient-derived PSCs from pancreatic cancer and chronic pancreatitis were compared using a gene expression microarray. Here, we found that endoplasmic reticulum aminopeptidase 2 (ERAP2), which resides in the endoplasmic reticulum (ER) membrane, was highly expressed in both cancer-associated PSCs and pancreatic cancer cells (PCCs). We found that high stromal ERAP2 expression is associated with a poor prognosis of PDAC patients. Knockdown of ERAP2 inhibited autophagy of PSCs and PCCs. In PSCs, inhibition of autophagy by ERAP2 knockdown led to inactivation of PSCs and attenuated tumor-stromal interactions. This process was mediated by ER stress and consequent IRE1α and PERK unfolded protein response (UPR) signaling pathways. In orthotopic models, ERAP2 knockdown in PSCs inhibited growth and fibrosis of xenografted tumor compared with coimplantation of PSCs without ERAP2 knockdown, and gemcitabine treatment further inhibited tumor growth. Our findings demonstrate a novel mechanism of PSCs activation regulated by autophagy. ERAP2 as a promising therapeutic target may provide a novel strategy for the treatment of PDAC.

2022-04-30 | GSE172168 | GEO

Gene expression profile at single cell level of mesenchymal cells and cancer-associated fibroblasts from mouse pancreas

Project description:Pancreatic stellate cells (PSCs) are components of normal pancreatic mesenchyme, and give rise to cancer-associated fibroblasts during pancreatic tumorigenesis. We used single cell RNA sequencing (scRNA-seq) to analyze PSCs and PSC-derived CAFs from normal pancreas and pancreatic cancer tissues, respectively.

2024-09-30 | GSE278162 | GEO

Expression data from HepG2 cells transfected with the Vitamin D Receptor (VDR) and activated by Vitamin D (calcitriol)

Project description:In the present study, we aimed to define the role of VDR in the overall lipid metabolism by transcriptomic and metabolomic analyses of human hepatocytes upon VDR activation by vitamin D (VitD) In this dataset we include the expression data obtained from HepG2 cells transfected with an insertless adenoviral vector or with an adenovirus encoding human VDR. Cells expressing VDR were treated with VitD or vehicle.

2020-04-01 | GSE138376 | GEO

Effect of calcipotriol treatment, chaetocin treatment and VDR knockdown on gene expression in BJ cells

Project description:To investigate the effect of calcipotriol treatment, chaetocin treatment and VDR knockdown on gene expression primary normal human fibroblasts, we treated BJ cells with 100 nM calcipotriol for 4 or 24 hours, 50 nM chaetocin for 24 hours, knocked down VDR with si RNA respectively. Then, we performed RNA-seq analysis.

2023-02-11 | GSE224311 | GEO

Non-canonical Hedgehog signaling via GLI2 promotes pancreatic stellate cell activation and fibrosis in chronic pancreatitis

Project description:Excessive Hedgehog (Hh) signaling activity contributes to fibrosis in multiple organs, however, its role in pancreatic stellate cell (PSC) activation and fibrosis development during chronic pancreatitis (CP) remains unclear. We demonstrate that GLI2 is upregulated in activated PSCs from CP patients and animal models. Specific deletion of Gli2, but not Smo, significantly alleviated fibrosis in CP models, indicating that CP is driven by non-canonical Hh signaling. Experiments on culture-activated primary PSCs reveal early nuclear translocation and increased GLI2 expression promptly after in vitro culture, with GLI2 being essential for PSC activation. SMO inhibition only reduces GLI2 activation in the short term, while activation of GLI2 by TGF-β/SMAD3 signaling explains the SMO-independent mechanisms leading to Hh activation in PSCs. Altogether, our data demonstrate the activation of the non-canonical Hh pathway in PSCs and indicate that GLI2 represents a promising therapeutic target for CP.

2024-11-13 | GSE281427 | 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