Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE223205 | GEO | 2023/09/18

REPOSITORIES: GEO

ACCESS DATA

Json Xml

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

Senescence defines a distinct subset of myofibroblasts that orchestrates immunosuppression in pancreatic cancer

Project description:Therapeutic resistance in PDAC is largely attributed to a unique tumor microenvironment embedded with an abundance of cancer associated fibroblasts (CAFs). Distinct CAF populations were recently identified, but the phenotypic drivers and specific impact of CAF heterogeneity remain unclear. In this study, we identify a subpopulation of senescent myofibroblastic CAFs (SenCAFs) in mouse and human PDAC. These SenCAFs are a subset of myofibroblastic CAFs that localize near tumors ducts, have distinct phenotypes and accumulate with PDAC progression. To assess the impact of endogenous SenCAFs in PDAC, we employed a LSL-KRASG12D;p53flox;p48-CRE;INK-ATTAC (KPPC-IA) mouse model of spontaneous PDAC with inducible senescent cell depletion. Senescence depletion with the KPPC-IA model or with the senolytic drug ABT263/Navitoclax, delayed tumor progression, reduced fibrosis, and relieved immune suppression in macrophages and T lymphocytes. Collectively, our findings demonstrate that SenCAFs promote PDAC progression and immune cell dysfunction.

2024-03-15 | GSE254384 | 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

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

Lorazepam stimulates IL-6 production and is associated with poor survival outcomes in pancreatic cancer

Project description:LOR is associated with worse progression-free survival (PFS) while alprazolam (ALP) is associated with improved PFS, in pancreatic cancer patients receiving chemotherapy. LOR promotes desmoplasia (fibrosis and extracellular matrix protein deposition), inflammatory signaling, and ischemic necrosis. GPR68 is preferentially expressed on human PDAC CAFs, and n-unsubstituted BZDs, such as LOR, significantly increase IL-6 expression and secretion in CAFs in a pH and GPR68-dependent manner. Conversely, ALP, and other GPR68 n-substituted BZDs decrease IL-6 in human CAFs in a pH and GPR68-independent manner. Across many cancer types, LOR is associated with worse survival outcomes relative to ALP and patients not receiving BZDs. We demonstrate that LOR stimulates fibrosis and inflammatory signaling, promotes desmoplasia and ischemic necrosis, and is associated with decreased pancreatic cancer patient survival.

2023-07-19 | GSE237649 | GEO

Deletion of Lats 1 and 2 in mouse pancreatic acinar cells

Project description:Mice with adult pancreatic acinar cell–specific deletion of Lats1&2 genes by using CreER/LoxP were generated. Pancreata were collected and profiled using RNA-seq. The RNA-sequencing data identified upregulation of pro-inflammatory and pro-fibrotic genes in Lats1&2 null pancreata, which may play important roles in stimulating PSC activation and promoting pancreatic fibrosis.

2019-07-26 | GSE111640 | GEO

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (KPC)

Project description:Cancer-associated fibroblasts (CAFs) give rise to desmoplastic stroma, which supports tumor progression and metastasis, and comprises up to 90% of the tumor mass in pancreatic cancer. Recent work by us and others has shown that CAFs are transcriptionally rewired by adjacent cancer cells to form heterogeneous subtypes. Whether this rewiring is differentially affected by different driver mutations in cancer cells is largely unknown. Here we address this question by dissecting and comparing the stromal landscape of BRCA-mutated and BRCA Wild-type (WT) pancreatic ductal adenocarcinoma (PDAC). We comprehensively analyze PDAC samples from a cohort of 42 patients by laser-capture microdissection, RNA-sequencing and multiplexed immunofluorescence, revealing different CAF subtype compositions in germline BRCA-mutated vs. BRCA-WT tumors. In particular, we detect an increase in a subset of Clusterin (CLU)-positive CAFs in BRCA-mutated tumors. Using cancer organoids, co-cultures and in-vivo models we show that loss of BRCA function in cancer cells leads to a transcriptional shift of pancreatic stellate cells from myofibroblastic into immune-regulatory CLU+ CAFs. This process is mediated through activation of heat-shock factor 1 (HSF1), the transcriptional regulator of Clu. Our findings unravel a new dimension of stromal heterogeneity, influenced by germline mutations in cancer cells, with direct translational implications for clinical research.

2022-10-10 | GSE200615 | GEO

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (CAF)

2022-10-10 | GSE200613 | GEO

BRCA mutational status shapes the stromal microenvironment of pancreatic cancer linking CLU+ CAF expression with HSF1 signaling (PSC)

2022-10-10 | GSE200616 | GEO

RRBS of pancreatic cancer cells derived from a genetically engineered mouse model, which harbor the inducible KrasG12D allele

Project description:Pancreatic adenocarcinoma (PDAC) is a lethal disease and it is the most common type of pancreatic cancer. Majority of the pancreatic cancers harbor alterations in the Kras gene. Currently there are no approved drugs that target Kras directly and it's downstream effect on the epigenome remains unknown. In this study, we investigated the epigenetic landscape of pancreatic cancer cells which harbor the inducible KrasG12D allele. We performed RNA-seq, ChIP-seq against 6 different histone marks, ATAC-seq and RRBS to assess the changes in the epigenome after oncogenic KrasG12D induction.

2021-09-06 | E-MTAB-10900 | biostudies-arrayexpress

OmicsDI is part of the ELIXIR infrastructure

OmicsDI is an Elixir interoperability service. Learn more ›

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