Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE172168 | GEO | 2022/04/30

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Disruption of pancreatic stellate cell myofibroblast phenotype promotes pancreatic tumour invasion.

Project description:In pancreatic ductal adenocarcinoma (PDAC), differentiation of pancreatic stellate cells (PSCs) into myofibroblast-like cancer-associated fibroblasts (CAFs) promotes fibrotic, therapy-resistant tumours. Conversely, suppression of CAFs can result in aggressive metastatic tumours. Here we show that the Rho-effector kinase protein kinase N2 (PKN2) is critical for PSC myofibroblast differentiation. Loss of PKN2 was associated with reduced PSC proliferation and contractility, retention of lipid droplets and decreased a-SMA stress fibres. PKN2 loss was also associated with a myofibroblast CAF to -like inflammatory CAF switch in the PSC matrisome signature both in vitro and in vivo. In spheroid co-cultures with PDAC cells, loss of PKN2 prevented PSC invasion but, counter-intuitively, promoted invasive cancer cell outgrowth. Further, deletion of PKN2 in the pancreatic stroma induced more locally invasive, orthotopic pancreatic tumours. Finally, we demonstrated that a PKN2KO PKN2 KO matrisome signature predicts poor outcome in pancreatic and other solid human cancers. Our data indicate that suppressing PSC myofibroblast differentiation function can limit important stromal tumour suppressive mechanisms, while promoting a switch to a cancer-supporting CAF phenotype.

2021-11-19 | GSE189027 | GEO

Extracellular matrix targeted mRNA profiles of PKN2 KO/WT mouse pancreatic stellate cell lines (PSCs) treated with TGF-b or vehicle control

2021-11-22 | GSE189245 | GEO

Role of Macrophage migration inhibitory factor (MIF) in pancreatic stellate cells (PSCs)

Project description:The presence of activated pancreatic stellate cells (PSCs) in the pancreatic ductal adenocarcinoma (PDAC) microenvironment plays a significant role in cancer progression. Macrophage migration inhibitory factor (MIF) is overexpressed in PDAC tissues and expressed by both cancer and stromal cells. The expression status of MIF and its receptors in PDAC- associated fibroblasts or PSCs and its pathophysiological roles are yet to be elucidated. The next-generation sequencing technique was adapted to check the effect of MIF absence on the expression of other genes in mice (mPSCs).

2022-09-28 | E-MTAB-9392 | biostudies-arrayexpress

Acid-base homeostasis orchestrated by NHE1 defines the pancreatic stellate cell phenotype in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) progresses in an organ with a unique pH landscape, where the stroma acidifies after each meal. We hypothesized that disrupting this pH landscape during PDAC progression triggers pancreatic stellate cells (PSCs) and cancer-associated fibroblasts (CAFs) to induce PDAC fibrosis. We revealed that alkaline environmental pH is sufficient to induce PSC differentiation to a myofibroblastic phenotype. We then mechanistically dissected this finding focusing on the involvement of the Na+/H+ exchanger NHE1. Perturbing cellular pH homeostasis by inhibiting NHE1 with cariporide partially alters the myofibroblastic PSC phenotype. To show the relevance of this finding in vivo, we targeted NHE1 in murine PDAC (KPfC). Indeed, tumor fibrosis decreases when mice receive the NHE1-inhibitor cariporide in addition to gemcitabine treatment. Moreover, the tumor immune infiltrate shifts from granulocyte-rich to more lymphocytic. Taken together, our study provides mechanistic evidence on how the pancreatic pH landscape shapes pancreatic cancer through tuning PSC differentiation.

2023-09-18 | GSE223205 | GEO

Hypoxia promotes an inflammatory phenotype of fibroblasts in pancreatic cancer

Project description:Pancreatic ductal adenocarcinoma (PDAC) is characterized by an extensive fibroinflammatory stromal reaction, which contributes to its hypovascular and hypoxic microenvironment. To assess the effects of hypoxia on fibroblast phenotype in an unbiased fashion, we performed RNA-sequencing profiling of mouse pancreatic stellate cells (PSCs) cocultured with mT3 PDAC cells exposed to normoxia (21% oxygen) or hypoxia (1% oxygen).

2022-09-14 | GSE199012 | GEO

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

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

RNA-sea of Smad4 wild-type or Smad4 knockout KvPC PDAC organoids from monocultures or co-cultures with pancreatic stellate cells and RNA-seq of flow-sorted PSCs from the same co-cultures.

Project description:RNA-sequencing of flow-sorted Smad4 wild-type (WT) or Smad4 knockout (KO) KvPC (i.e. KRASG12V; p53 mutant) pancreatic ductal adenocarcinoma (PDAC) organoids from monocultures or co-cultures with pancreatic stellate cells (PSCs) and RNA-sequencing of flow-sorted PSCs from the same co-cultures. We investigated changes in transcriptome in Smad4 KO KvPC PDAC organoids compared to Smad4 WT KvPC PDAC organoids in monoculture or in co-culture with PSCs. We also investigated the changes in transcriptome in PSCs co-cultured with Smad4 WT or Smad4 KO KvPC PDAC organoids.

2024-12-02 | GSE263081 | GEO

RNA-sea of Smad4 wild-type or Smad4 knockout KPC PDAC organoids from monocultures or co-cultures with pancreatic stellate cells and RNA-seq of flow-sorted PSCs from the same co-cultures.

Project description:RNA-sequencing of flow-sorted Smad4 wild-type (WT) or Smad4 knockout (KO) KPC (i.e. KRASG12D; p53 mutant) pancreatic ductal adenocarcinoma (PDAC) organoids from monocultures or co-cultures with pancreatic stellate cells (PSCs) and RNA-sequencing of flow-sorted PSCs from the same co-cultures. We investigated changes in transcriptome in Smad4 KO KPC PDAC organoids compared to Smad4 WT KPC PDAC organoids in monoculture or in co-culture with PSCs. We also investigated the changes in transcriptome in PSCs co-cultured with Smad4 WT or Smad4 KO KPC PDAC organoids.

2024-12-02 | GSE263080 | GEO

Single-cell RNA-sequence reveals the transcriptional dynamics of tumor immune microenvironment by autophagy inhibition in cancer cells

Project description:In this study, we investigated the impact of autophagy inhibition in cancer cell on the tumor immune microenvironment (TIME) of orthotopic syngeneic pancreatic ductal adenocarcinoma (PDAC) tumors. Dendritic cells (DCs) in the cancer cell autophagy inhibited tumors showed significantly higher expression of genes related to DC functions such as antigen-presentation, migration, IFN response, compared to control tumors. Our results indicate that autophagy inhibition in cancer cells induce the enhancement of adoptive tumor immunity via DC activation in PDAC.

2024-09-11 | GSE233663 | 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