Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

Loss of PARP7 increases IFN-I signalling preventing pancreatic tumour growth by enhancing immune cell infiltration

ABSTRACT: Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer, and despite low incidence rates, it remains the sixth leading cause of cancer related deaths worldwide. Immunotherapy, which aims to enhance the immune system’s ability to recognize and eliminate cancer cells, has emerged as a promising approach in the battle against PDAC. PARP7, a mono-ADP-ribosyltransferase, is a negative regulator of the type I interferon (IFN-I) pathway, thereby reducing antitumour immunity. By characterizing murine pancreatic cancer cells, we found that loss of PARP7 elevated the levels of interferon stimulated gene factor 3 (ISGF3) and its downstream target genes, even in the absence of STING. We also observed that cancer cells deficient in PARP7 resulted in smaller tumours when injected into wildtype mice. Transcriptomic analyses revealed that tumours knocked out for Parp7 (Parp7KO) had increased expression of genes involved in immunoregulatory interactions and interferon signalling pathways. Characterization of tumour infiltrating leukocyte (TIL) populations showed that Parp7KO tumours had higher proportions of natural killer cells, CD8+ T cells and a lower proportion of anti-inflammatory macrophages (M2). The overall TIL profile of Parp7KO tumours was suggestive of a better response to anti-PD-1 immune checkpoint therapy. Our data show that loss of PARP7 reduces PDAC tumour growth by increasing the infiltration of immune cells and enhancing antitumor immunity. These findings provide support to pursue PARP7 as a therapeutic target for PDAC

ORGANISM(S): Mus musculus

PROVIDER: GSE276293 | GEO | 2025/01/03

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Shared Molecules

Only show the datasets with similarity scores above: 0.5

Threshold

0.5

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

Gene expression analysis of TIL rich HPV driven head and neck tumours reveals a distinct B-cell signature when compared to HPV independent tumours.

Project description:Purpose: Human papilloma virus (HPV) associated head and neck squamous cell carcinoma (HNSCC) has a better prognosis than HPV(-) negative cancer. This may be due, in part, to the higher number of tumour infiltrating lymphocytes (TIL) in HPV(+) tumours. We used RNAseq to evaluate whether these differences in clinical behaviour could be explained simply by a numerical difference in TILs or whether there was a fundamental difference between TILs in these two settings. Patients and methods: Twenty-three consecutive HNSCC cases with high and moderate TIL density were subjected to RNAseq analysis. Differentially expressed genes (DEG) between 10 HPV(+) and 13 HPV(-) tumours were identified with EdgeR. Immune subset analysis was performed using, FAIME (Functional Analysis of Individual Microarray Expression) and Immune gene transcript count analysis. Results: 1634 genes were differentially expressed. There was a dominant immune signature in HPV(+) tumours. After normalizing expression profiles for numerical differences in T cells and B cells, 437 significantly DEGs still remained. A B-cell associated signature emerged, which segregated HPV(+) from HPV(-) cancers and included CD200, STAG3, GGA2, SPIB and ADAM28. Differential expression of these genes was confirmed by real-time quantitative PCR and immunohistochemistry. Conclusion: In our dataset, the difference associated with T-cells between patients with HPV(+) and (-) HNSCC was predominantly numerical. However, when TIL numbers are corrected, a distinct differential B-cell signature was revealed. mRNA profiles of 10 HPV driven (HPV+) and 13 HPV independant (HPV-) head and neck squamous cell carcinoma (HNSCC) tumours were generated by RNA-Seq, using Illumina HiSeq 2000.

2016-09-01 | E-GEOD-72536 | biostudies-arrayexpress

Hierarchical clustering of PDAC cell lines

Project description:Hierarchical clustering of pancreatic cancer cell lines based on differentially regulated genes between mesenchymal and epithelial PDAC cells derived from primary tumours and metastases from KrasG12D-driven mouse models of pancreatic cancer.

2022-11-19 | E-MTAB-8173 | biostudies-arrayexpress

SWATH-MS based proteomic profiling of Pancreatic Ductal Adenocarcinoma tumours reveals the interplay between the extracellular matrix and related intracellular pathways

Project description:Pancreatic cancer accounts for 2.8% of new cancer cases worldwide and is projected to become by 2030 the second leading cause of cancer-related deaths. Patients of African ancestry appear to be at an increased risk for pancreatic ductal adenocarcinoma (PDAC), with worse severity and outcomes. The purpose of this study was to map the proteomic and genomic landscape of a cohort of PDAC patients of African ancestry. Thirty tissues (15 tumours and 15 normal adjacent tissues) were obtained from consenting South African PDAC patients. Optimisation of the sample preparation method allowed for the simultaneous extraction of high-purity protein and DNA for SWATH-MS and OncoArray SNV analyses. We quantified 3402 proteins with 49 upregulated and 35 downregulated proteins at a minimum 2.1 fold change and FDR adjusted p-value (q-value) ≤ 0.01 when comparing tumour to normal adjacent tissue. Many of the upregulated proteins in the tumour samples are involved in extracellular matrix formation (ECM) and related intracellular pathways. Proteins such as EMIL1, ZCCHV and KBTB2 involved in the regulation of ECM proteins were observed to be dysregulated in pancreatic tumours. Approximately 11% of the dysregulated proteins, including ISLR, BP1, PTK7 and OLFL3, were predicted to be secretory proteins. Additionally, we identified missense mutations in some upregulated proteins, such as MYPN, ESTY2 and SERPINB8. These findings help in further elucidating the biology of PDAC and may aid in identifying future plausible markers for the disease.

2020-09-30 | PXD019549 | Pride

Establishment and Characterisation by Expression Microarray of Patient Derived Xenograft Panel of Human Pancreatic Adenocarcinoma Patients

Project description:mRNA expression profiling of pancreatic cancer, comparing adjacent normal tissue, patient tumour and first generation patient derived xenograft tumours Fresh tumour samples for human pancreatic adenocarcinoma patients were implanted in SCID mice. 70% of these pancreatic ductal adenocarcinoma patients grew as PDX tumours, confirmed by histopathology. Frozen samples from F1 PDX tumours could be later successful passaged in SCID mice to F2 PDX tumours. The human origin of the PDX was confirmed using human specific antibodies; however, the stromal component was replaced by murine cells. Cell lines were successfully developed from three PDX tumours. RNA was extracted from 8 PDX tumours and where possible, corresponding primary tumour and adjacent normal tissues. mRNA profiles of tumour vs F1 PDX and normal vs tumour were compared by Affymetric microarray analysis

2019-12-12 | GSE141873 | GEO

miRNA expresion data from PDAC Tumour, adjacent normal and PDX tissue samples

2023-03-06 | GSE207345 | GEO

TLR2 promotes tumour proliferation in KRAS-dependant PDAC in the absence of ARF6

Project description:Metastasis is responsible for nearly 90% of all cancer-related deaths. Despite global efforts to prevent aggressive tumours, cancers such as pancreatic ductal adenocarcinoma (PDAC) are poorly diagnosed in the primary stage, resulting in lethal metastatic disease. RAS mutations are known to promote tumour spread, with mutant KRAS present in almost 90% of cases. Until recently, mutant KRAS remained untargeted and, despite the recent development of inhibitors, results show that tumour cells develop resistance. Another strategy for targeting mutant KRAS-dependent PDAC metastasis may come from targeting the downstream effectors of KRAS. One such axis, which controls tumour proliferation, invasiveness and immune evasion, is represented by ARF6-ASAP1. Here we show that targeting ARF6 results in adaptive rewiring that can restore proliferation and invasion potential over time. Using time-series RNA and ATAC sequencing approaches, we identified TLR-dependent NFκB, TNFα and hypoxia signalling as key drivers of adaptation in ARF6-depleted KRAS-dependent PDAC. Using in vitro and in vivo assays, we show that knocking down TLR2 with ARF6 significantly reduces proliferation, migration and invasion. Taken together, our data shed light on a novel co-targeting strategy with the therapeutic potential to counteract PDAC proliferation and metastasis.

2023-12-02 | GSE247513 | GEO

Interventional hydrogel microsphere vaccine as an immune amplifier for activated antitumour immunity after ablation therapy

Project description:Current chemotherapy or immunotherapy regimens for pancreatic cancer are limited. Although minimally invasive irreversible electroporation (IRE) ablation is a promising option for unresectable pancreatic cancers, the typical immunosuppressive tumour microenvironment promotes immune evasion and rapid tumour recurrence. Thus, triggering efficient amplification of endogenous adaptive antitumour immunity is critical for improving immunotherapy after ablation therapy. Here, we developed a hydrogel microsphere vaccine as an immune amplifier for post-ablation cancer immunotherapy. The vaccine acts as a general immune amplifier to trigger a rocket-like amplification of the cDC1-mediated antigen cross-presentation cascade, resulting in dramatic amplification of the antitumour immunity of endogenous CD8+ T cells. We also showed that the hydrogel microsphere vaccine promoted the transformation of pancreatic cancer from "cold" to "hot" tumours in a safe and efficient manner, significantly increased the survival of mice bearing orthotopic pancreatic tumours, and induced strong systemic antitumour immunity, which inhibited the growth of distant metastases.

2023-05-22 | GSE215417 | GEO

Human pancreatic adenocarcinoma contains a side population resistant to gemcitabine

Project description:BACKGROUND: Therapy resistance remains one of the major challenges to improve the prognosis of patients with pancreatic cancer. Chemoresistant cells, which potentially also display cancer stem cell (CSC) characteristics, can be isolated using the side population (SP) technique. Our aim was to search for a SP in human pancreatic ductal adenocarcinoma (PDAC) and to examine its chemoresistance and CSC phenotype. RESULTS: A SP was identified in all PDAC samples, expanded and analyzed as first-generation xenografts. This SP was more resistant to gemcitabine than the other tumour cells as analyzed in vivo. Whole-genome expression profiling of the SP revealed upregulation of genes related to therapy resistance, apoptotic regulation and epithelial-mesenchymal transition. In addition, the SP displayed higher tumourigenic (CSC) activity than the other main tumour cell population (MP) as analyzed in vitro by sphere-forming capacity. CONCLUSION: We identified a SP in human PDAC and uncovered a chemoresistant and CSC-associated phenotype. This SP may represent a new therapeutic target in pancreatic cancer. Micro-array analysis was performed on SP and MP samples of 5 xenografts, grown from 5 different human PDAC samples.

2016-01-04 | E-GEOD-36563 | biostudies-arrayexpress

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