Mus musculus
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA353591 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:We found that BAP1 (BRCA1 Associated Protein-1) shows loss of heterozygosity in over 25% of pancreatic cancer patients and functions as tumor suppressor. Conditional deletion of Bap1 in murine pancreas led to genomic instability, accumulation of DNA damage, and an inflammatory response that evolved to pancreatitis with full penetrance. Concomitant expression of oncogenic KrasG12D led to malignant transformation and development of invasive and metastatic pancreatic cancer. At the molecular level, BAP1 maintains the integrity of the exocrine pancreas by regulating genomic stability and its loss confers sensitivity to radio- and platinum-based therapies.
2020-04-14 | GSE121709 | GEO
Project description:GATA6 is a master regulator of differentiation in the pancreas and its expression levels determine the two main molecular subtypes of pancreatic cancer. High GATA6 contributes to the “classical” pancreatic cancer subtype, which is associated with a higher degree of tumor differentiation and better disease prognosis. However, why GATA6 expression varies across pancreatic cancers and what regulate GATA6 expression remain elusive. Here we report that the oncogenic KRAS-activated ERK signaling suppresses GATA6 transcription in pancreatic cancers. GATA6 mRNA levels inversely correlated with KRAS/ERK activity in pancreatic tumors. A genome-wide CRISPR screen in a GATA6-EGFP reporter knockin cell line identified JUNB as the ERK-regulated transcriptional repressor for GATA6. Active ERK stabilizes JUNB protein while KRAS/ERK inhibition led to ubiquitin-independent proteasomal degradation of JUNB and increased transcription of GATA6. Up-regulation of GATA6 enhanced chemosensitivity of pancreatic cancer cells and KRAS/ERK inhibitors synergized with chemotherapy in a GATA6-dependent manner. Our study identifies how oncogenic KRAS/ERK signaling suppresses GATA6 to cause dedifferentiation in pancreatic cancer. Combining KRAS/ERK inhibitors with standard-of-care chemotherapies could be a promising therapeutic strategy for treating pancreatic cancers.
2025-11-20 | GSE307506 | GEO
Project description:Pancreatic cancer is characterised by the prevalence of oncogenic mutations in KRAS. Previous studies have reported that altered Kras gene dosage drives progression and metastatic incidence in pancreatic cancer. While the role of oncogenic KRAS mutation is well characterised, the relevance of the partnering wild-type KRAS allele in pancreatic cancer is less well understood and controversial. Using in vivo mouse modelling of pancreatic cancer, we demonstrate that wild-type Kras restrains the oncogenic impact of mutant Kras, and drastically impacts both Kras-mediated tumourigenesis and therapeutic response. Mechanistically, deletion of wild-type Kras increases oncogenic Kras signalling through the downstream MAPK effector pathway, driving pancreatic intraepithelial neoplasia (PanIN) initiation. In addition, in the KPC mouse model, a more aggressive model of pancreatic cancer, loss of wild-type KRAS leads to accelerated initiation but delayed tumour progression. These tumours had altered stroma, downregulated Myc levels and an enrichment for immunogenic gene signatures. Importantly, loss of wild-type Kras sensitises Kras mutant tumours to MEK1/2 inhibition though tumours eventually become resistant and then rapidly progress. This study demonstrates the repressive role of wild-type Kras during pancreatic tumourigenesis and highlights the critical impact of the presence of wild-type KRAS on tumourigenesis and therapeutic response in pancreatic cancer.
2024-09-22 | GSE277392 | GEO
Project description:Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (part 2)
| PRJNA231035 | ENA
Project description:Yap1 activation enables bypass of oncogenic Kras addiction in pancreatic cancer (part 1)
| PRJNA231036 | ENA
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-10901 | biostudies-arrayexpress
Project description:SNAIL is a key transcriptional regulator in embryonic development and cancer. Its effects in physiology and disease are believed to be linked to its role as a master regulator of epithelial-to-mesenchymal transition (EMT). Here, we report EMT-independent oncogenic SNAIL functions in cancer. Using genetic models, we systematically interrogated SNAIL effects in various oncogenic backgrounds and tissue types. SNAIL related phenotypes displayed remarkable tissue- and genetic context-dependencies, ranging from protective effects as observed in KRAS- or WNT-driven intestinal cancers, to dramatic acceleration of tumorigenesis, as shown in KRAS-induced pancreatic cancer. Unexpectedly, SNAIL-driven oncogenesis was not associated with E-cadherin downregulation or induction of an overt EMT program. Instead, we show that SNAIL induces bypass of senescence and cell cycle progression through p16INK4A-independent inactivation of the Retinoblastoma (RB)-restriction checkpoint. Collectively, our work identifies novel non-canonical EMT-independent functions of SNAIL and unravel its complex context-dependent role in cancer.
2022-12-13 | PXD038726 | Pride
Project description:Mutations in KRAS occur in a variety of tumors of epithelial origin, driving the oncogenic phenotype.The NF-kB transcription factor pathway is important for oncogenic RAS to transform cells and to drive tumorigenesis in animal models. Recently TAK1, an upstream regulator of IKK which controls canonical NF-kB, was shown to be important for chemoresistance in pancreatic cancer and for regulating KRAS+ colorectal cancer cell growth and survival. Here we show that GSK-3alpha is upregulated by KRAS leading to interaction with TAK1 to stabilize the TAK1/TAB complex to promote IKK activity. Additionally, GSK-3alpha is required for promoting critical non-canonical NF-kB signaling in pancreatic cancer cells. Pharmacologic inhibition of GSK-3 suppresses growth of human pancreatic tumor explants, consistent with loss of expression of genes such as c-myc and TERT. These data identify GSK-3alpha as a key downstream effector of oncogenic RAS via its ability to coordinately regulate distinct NF-kB signaling pathways GSK-3 inhibition at 2 and 8 hours
2013-05-31 | E-GEOD-42559 | biostudies-arrayexpress
Project description: Not available
| S-EPMC8784167 | biostudies-literature
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-10896 | biostudies-arrayexpress