Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

ZEB1, a novel junctional adhesion molecule A regulator, impacts sensitivity of pancreatic cancer-associated fibroblasts to reovirus

ABSTRACT: Oncolytic virus (OV) therapy is a promising treatment for various tumors. However, in pancreatic ductal adenocarcinoma (PDAC), the high abundance of cancer-associated fibroblasts (CAFs) can limit OV therapy efficacy by impairing viral spread and anti-tumor immunity. We have previously shown that oncolytic reovirus infection of CAFs depends on the expression of the reovirus entry receptor junctional adhesion molecule A (JAM-A), which is not or lowly expressed in most PDAC CAFs. We propose that increasing JAM-A expression on CAFs will boost viral spread in a tumor. However, there are currently no known regulators of JAM-A expression. Therefore, we performed a genome-wide CRISPR-Cas9 knockout screen to identify novel regulators of JAM-A expression. Ablation of the top negative regulator, zinc finger E-box binding homeobox 1 (ZEB1), in pancreatic fibroblasts led to strong JAM-A upregulation. We show that ZEB1 directly regulates JAM-A expression by binding to the enhancer-box (E-box) regions located within the JAM-A promoter. Importantly, ZEB1 ablation increased the sensitivity of fibroblasts to reovirus infection and subsequent cell death. Our work provides a novel overview of genes regulating JAM-A expression and provides a rational approach of combining ZEB1 inhibition with reovirus therapy to target both CAFs and tumor cells in stroma-rich tumors such as PDAC.

ORGANISM(S): Homo sapiens

PROVIDER: GSE290358 | GEO | 2025/10/29

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Dataset's files

Source:

			Action	DRS
		Other

Items per page:

1 - 1 of 1

Similar Datasets

Microarray analysis of human NK cells following oncolytic reovirus treatment of peripheral blood mononuclear cells (PBMC)

Project description:Oncolytic viruses (OV) kill tumour cells directly and induce anti-tumour immunity. We analysed gene expression profiles in human NK cells following treatment of PBMC with oncolytic reovirus in vitro.

2022-01-03 | E-MTAB-9826 | biostudies-arrayexpress

Identifying genetic expression patterns as marker for sensitivity to oncolytic viruses using patient-derived pancreatic ductal adenocarcinoma organoids

Project description:Purpose: Pancreatic ductal adenocarcinoma (PDAC) is among the deadliest cancers, with a poor prognosis. Viro-immunotherapy using oncolytic viruses (OVs) represents a promising treatment for PDAC. However, PDACs from different patients respond differently to OV therapies, highlighting the need for predictive biomarkers to optimize outcomes. This study aimed to identify gene expression profiles (GEPs) that could serve as predictors for OV sensitivity. Experimental design: Patient-derived organoids (PDOs) from ten PDAC patients were assessed for sensitivity to various OVs: Newcastle Disease Virus, a Reovirus strain entering cells independently of JAM-A expression, the Edmonston vaccine strain of Measles Virus, and a gorilla-derived adenovirus. To identify GEPs with predictive value, OV sensitivity was correlated with the transcriptome of uninfected PDOs. These GEPs were analyzed in the Gene Ontology database to reveal biological processes associated with them. Results: PDOs showed heterogenic responses to OVs, with nine of ten being sensitive to at least one. Analysis of the generated GEPs using the Gene Ontology database identified intracellular aberrations as the primary determinant of OV sensitivity. Sensitivity to all OVs was associated with GEPs related to embryonic development, while varied sensitivity of the ten PDOs to four OVs was linked to cell cycle regulation, metabolism, and proliferation. Conclusions: This study revealed that OV sensitivity was associated with GEPs comprising genes involved in multiple biological processes. Further investigation into screening tumors for the identified GEPs may yield biomarkers for selecting the most effective OV for PDAC. This approach is a stepping stone toward personalized OV treatments.

2025-02-11 | GSE288907 | GEO

Quantitative Proteome Responses to Oncolytic Reovirus in GM-CSF and M-CSF-Differentiated Bone Marrow-Derived Cells

Project description:To explore reovirus-macrophage interactions, we performed tandem mass tag (TMT)-based quantitative temporal proteomics on mouse bone marrow-derived macrophages (BMMs) generated with 2 cytokines, M-CSF and GM-CSF, representing anti- and pro-inflammatory macrophages, respectively. We quantified 6,863 proteins across five time points in duplicate, comparing M-CSF (M-BMM) and GM-CSF (GM-BMM) in response to OV. We find that GM-BMMs have lower expression of key intrinsic proteins that facilitate an anti-viral immune response, express higher levels of reovirus receptor protein JAM-A and are more susceptible to oncolytic reovirus infection compared to M-BMMs. Interestingly, although M-BMMs are less susceptible to reovirus infection and subsequent cell death, they initiate an anti-reovirus adaptive T cell immune response comparable to that of GM-BMMs. Taken together, these data describe distinct proteome differences between these two macrophage populations in terms of their ability to mount anti-viral immune responses.

2020-01-07 | PXD015203 | Pride

FAK activity in cancer-associated fibroblasts is a prognostic marker and a druggable key metastatic player in pancreatic cancer

Project description:Cancer-associated fibroblasts (CAFs), although considered as the most abundant pancreatic ductal adenocarcinoma (PDAC) stromal cells playing a critical role in tumor progression and chemoresistance, are not yet directly druggable. Here we report that focal adhesion kinase (FAK) activity (evaluated based on 397 tyrosine phosphorylation level) in CAFs is highly increased compared to its activity in fibroblasts from healthy pancreas. Fibroblastic FAK activity is an independent prognostic marker for disease free and overall survival of PDAC patients (cohort of 120 PDAC samples). Genetic inactivation of FAK within fibroblasts (FAK-kinase-dead, KD) reduces fibrosis and immunosuppressive cell number within primary tumor and dramatically decreases tumor spread. Mechanistically, pharmacologic and genetic fibroblastic FAK inactivation reduces fibroblast migration/invasion, decreases extracellular matrix (ECM) expression and deposition by CAFs, and negatively impacts M2 macrophage polarization and migration. Thus, FAK activity within CAFs appears as an independent PDAC prognostic marker and a druggable driver of tumor cell invasion.

2020-08-19 | PXD018899 | Pride

Reshaping of the MHC-I ligandome in response to reovirus-based cancer immunotherapy

Project description:Oncolytic viruses (OVs), known for their cancer-killing characteristics, overturn tumor-associated defects in antigen presentation through the MHC class I pathway and induce protective neo antitumor CD8 T cell responses. Nonetheless, whether OVs shape the tumor MHC-I ligandome remains unknown. Here, we investigated if an OV induces the presentation of novel MHC I-bound tumor antigens (termed tumor MHC-I ligands). Using comparative mass spectrometry (MS)-based MHC-I ligandomics, we determined differential tumor MHC-I ligand expression following treatment with oncolytic reovirus in a murine ovarian cancer model. In vitro we found that reovirus induces the presentation of tumor MHC-I ligands in cancer cells. Concurrent multiplexed quantitative proteomics revealed that the changes in tumor MHC-I ligand presentation were mostly independent of reovirus-induced alterations of their source proteins. In an in vivo model, tumor MHC-I ligands were induced by reovirus in tumors but also, more importantly, analysis of spleens (a source of antigen-presenting cells) showed exclusive induction of most MHC-I ligands occurred in tumor-bearing mice. Finally, IFNγ assays demonstrated immunogenicity of the reovirus-induced MHC-I ligands. OV-induced MHC-I responses may be exploited in combinatorial approaches to promote the efficacy of cancer immunotherapies.

2019-05-20 | PXD013066 | Pride

Expression data from gemcitabine treated pancreatic CAFs

Project description:Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer associated fibroblasts (CAFs). CAFs promote tumor growth, metastasis and treatment resistance. We aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAFs) were generated by continuous incubation in 100nM gemcitabine. Gene expression differences between treatment naÃ¯ve CAFs (N-CAFs) and R-CAFs were compared by array analysis. Immortalized human pancreatic CAFs were grown for 30 days in either control media or media containing 100nM gemcitabine. RNA was then isolated and hybidized on U133 Plus 2.0 Affymetrix arrays.

2016-03-09 | E-GEOD-78982 | biostudies-arrayexpress

Biomarker Screen for Efficacy of Oncolytic Virotherapy in Patient-derived Pancreatic Cancer Cultures

Project description:Pancreatic ductal adenocarcinoma (PDAC) is a tumour entity with unmet medical need. To assess the therapeutic potential of oncolytic virotherapy (OVT) against PDAC, different oncolytic viruses (OVs) are currently investigated in clinical trials. However, systematic comparisons of these different OVs in terms of efficacy against PDAC and biomarkers predicting therapeutic response are lacking. We screened fourteen patient-derived PDAC cultures for their sensitivity to five clinically relevant OVs, namely serotype 5 adenovirus Ad5-hTERT, herpes virus T-VEC, measles vaccine strain MV-NIS, reovirus jin-3, and protoparvovirus H 1PV using live cell analysis, quantification of viral genome/gene expression, cell viability as well as cytotoxicity assays. Sensitivity was correlated with transcriptome profiles to identify potential predictive biomarkers for response to OVT. Patient-derived PDAC cultures showed individual response patterns to OV treatment. Twelve of fourteen cultures were responsive to at least one OV, with no single OV proving superior or inferior across all cultures. Known host factors for distinct viruses were retrieved as potential biomarkers. Compared to the basal-like molecular subtype, the quasi-mesenchymal subtype of PDAC was more sensitive to H-1PV, jin-3, and T-VEC. Expression of viral entry receptors did not correlate with sensitivity to OV treatment. Rather, cellular pathways controlling immunological, metabolic, and proliferative signalling appeared to determine outcome. For instance, high baseline expression of interferon-stimulated genes (ISGs) correlated with relative resistance to oncolytic measles virus, whereas cGAS expression was associated with exceptional response. Combination treatment of MV-NIS with a cGAS inhibitor improved tumour cell killing in several PDAC cultures.

| EGAS00001007001 | EGA

Single-Cell Analysis of Human Pancreatic Ductal Adenocarcinoma

Project description:<p>Cancer-associated fibroblasts (CAFs) are major players in the progression and drug resistance of pancreatic ductal adenocarcinoma (PDAC). CAFs constitute a diverse cell population consisting of several recently described subtypes, although the extent of CAF heterogeneity has remained undefined. Here we employ single-cell RNA-sequencing to thoroughly characterize the neoplastic and tumor microenvironment content of human PDAC tumors. Six human PDAC tumor specimens from six patients were collected, and processed for single-cell RNA-sequencing analysis. Adjacent-normal pancreas tissue was also collected from two of the patients. Tumor samples were digested, and fluorescence-activated cell sorting was used to isolate viable cells. For one tumor sample, viable, CD45-negative, CD31-negative, and EpCAM-negative cells were also isolated to enrich for CAFs. The 10X Chromium platform was then used to isolate single cells for RNA-sequencing analysis. This work has demonstrated the differences in immune cell populations between adjacent-normal and tumor tissues, and identified subpopulations of epithelial cells and CAFs present in PDAC tumors. This high-throughput analysis is a resource to better understand the cell populations present in PDAC, and may ultimately aid in the development of more effective therapies for this deadly malignancy.</p>

| phs001840 | dbGaP

The heterogeneous sensitivity of pediatric brain tumors to different oncolytic viruses is predicted by unique gene molecular profiles

Project description:Despite decades of research, the prognosis of high-grade pediatric brain tumors (PBTs) remains dismal, however, recent cases of favorable clinical responses were documented in clinical trials using oncolytic viruses (OVs). Therefore, we employ four different species of OVs: adenovirus Delta24-RGD, herpes simplex virus rQNestin34.5v1, reovirus R124 and the non-virulent Newcastle Disease Virus rNDV-F0-GFP against three entities of PBTs (high-grade gliomas, atypical teratoid/rhabdoid tumors and ependymomas) to determine their in vitro efficacy. These four OVs were screened on 14 patient-derived spheroids and the degree of oncolysis was assessed using an ATP-based assay. Subsequently, the observed viral efficacies were correlated to whole transcriptome data and Gene Ontology analysis was performed. Although no significant tumor type-specific OV efficacy was observed, whole transcriptome analysis revealed the intrinsic biological processes that associated with OV efficacy. The predictive power of those molecular profiles was further validated by screening the OV in vitro efficacy on additional PBTs. In summary, our results demonstrate OV susceptibility of multiple patient-derived PBT entities and the ability to predict in vitro responses to OVs using unique molecular profiles. Those profiles highlight the cellular intrinsic factors for potent oncolysis, that could potentially allow stratification of patients and lead to improved OV responses.

2024-04-28 | GSE260516 | GEO

Expression data from gemcitabine treated pancreatic CAFs

Project description:Pancreatic ductal adenocarcinoma (PDAC) has a characteristically dense stroma comprised predominantly of cancer associated fibroblasts (CAFs). CAFs promote tumor growth, metastasis and treatment resistance. We aimed to investigate the molecular changes and functional consequences associated with chemotherapy treatment of PDAC CAFs. Chemoresistant immortalized CAFs (R-CAFs) were generated by continuous incubation in 100nM gemcitabine. Gene expression differences between treatment naïve CAFs (N-CAFs) and R-CAFs were compared by array analysis.

2016-03-09 | GSE78982 | 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