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Effects of EZH2 ablation on promoter accessibility in mouse PDAC lines derived from KrasG12D/PEC/IkkαΔPEC tumors

ABSTRACT: Effects of EZH2 ablation on promoter accessibility in mouse PDAC lines derived from KrasG12D/PEC/IkkαΔPEC tumors

PROVIDER: PRJNA623922 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR11511117_1.fastq.gz	Fastqsanger.gz
	SRR11511117_2.fastq.gz	Fastqsanger.gz
	SRR11511118_1.fastq.gz	Fastqsanger.gz
	SRR11511118_2.fastq.gz	Fastqsanger.gz
	SRR11511119_1.fastq.gz	Fastqsanger.gz

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Effects of EZH2 ablation on promoter accessibility in mouse PDAC lines derived from KrasG12D/PEC/IkkαΔPEC tumors

Project description:We analyzed chromatin accessibility genome wide in EZH2KO and control cells derived from PDAC tumors of KrasG12D/PEC-IkkαΔPEC PDAC model mice to gain insight how the ablation of EZH2 affects the accessibility of genes involved in PDAC tumorigenesis.

2021-12-31 | GSE148335 | GEO

Next Generation Sequencing Quantitative Analysis of altered expression of genes in KRASG12D PDAC tissues

Project description:KRAS mutation is the most frequently mutated oncogene, occurring in approximately 90% of patients with PDAC, where KRASG12D is the most common allele in PDAC. Recent studies revealed that KRASG12D mutation caused the aberrant gene expression profile by regulating RNA processing to drive tumor progression (9, 17). However, the role of the KRASG12D mutation in triggering the circRNA process during tumor development remains unknown. Our study aims to explore the genes that regulates circRNA biogenesis in the LN metastasis of PDAC.

2023-09-20 | GSE234927 | GEO

mTORC1 and mTORC2 converge on the Arp2/3 complex to promote KrasG12D-induced acinar-to-ductal metaplasia and early pancreatic carcinogenesis

Project description:Oncogenic KrasG12D, a driver mutation of pancreatic ductal adenocarcinoma (PDAC), induces neoplastic transformation of acinar cells through acinar-to-ductal metaplasia (ADM). Here, we show that both functional complexes of mTOR (mechanistic target of rapamycin kinase, mTORC1 and mTORC2) are specifically activated in ADM. Murine models uncover that mTORC1 and mTORC2 cooperate to promote KrasG12D-driven ADM development. Proteomic analyses identify Arp2/3 complex, an actin nucleator, as the common downstream effector: mTORC1 is responsible for the protein synthesis of Rac1 and Arp3 while mTORC2 promotes the Arp2/3 complex activity via Akt/Rac1 signalling. Genetic ablation of Arp2/3 complex completely arrests KrasG12D-driven ADM development. The Arp2/3 complex-mediated y-branching of actin network promotes the basolateral spread of filamentous actin, which is indispensable for acinar cells-initiated carcinogenesis. Induced by oncogenic KrasG12D, ADM is a metaplastic phenotype of acinar cells that requires extensive actin rearrangements. mTORC1 and mTORC2, downstream targets of KrasG12D, have well-established oncogenic functions in PDAC development. The actin-related protein 2/3 (Arp2/3) complex is the first identified actin nucleator. Regarded as textbook knowledge, it is activated by EGFR/Rac1 signalling to promote the polymerisation of branched actin filaments from pre-existing filaments in numerous biological contexts. Hereby, we identify that mTORC1 and mTORC2 attain a dual, yet non-redundant, regulatory role in promoting Arp2/3 complex function, which is responsible for generating basolateral filamentous actin in ADM. Thus, the role of Arp2/3 complex fills up the missing gap between putative oncogenic signals and actin dynamics underlying PDAC initiation.

2021-01-07 | PXD018296 | Pride

EZH2 deletion does not impact acinar cell regeneration but restricts progression to pancreatic cancer in mice [ChIP-seq]

Project description:Enhancer of Zeste Homologue 2 (EZH2) is part of the Polycomb Repressor Complex 2, which induces trimethylation of lysine 27 on histone 3 (H3K27me3) and promotes genes repression. EZH2 is overexpressed in many cancers including pancreatic ductal adenocarcinoma (PDAC). Previous studies in mice attributed both pro-oncogenic and tumor suppressive functions to EZH2. Deletion of the EZH2 enhancesde novoKRAS-driven neoplasia following pancreatic injury by preventing acinar cell regeneration, while increased EZH2 expression in PDAC is correlated to poor prognosis, suggesting a context-dependant effect for EZH2 in PDAC progression. In this study, we examined EZH2 function in pre- and early neoplastic stages of PDAC. Using an inducible model to generate deletion of EZH2 only in adult acinar cells (EZH2DSET), we showed loss of EZH2 activity did not prevent acinar cell regeneration in the absence of oncogenic KRAS (KRASG12D), nor lead to increased PanIN formation in the presence of KRASG12Din adult mice. However, loss of EZH2 did reduce recruitment of inflammatory cells and, when combined with a PDAC model, promoted widespread PDAC progression. Loss of EZH2 function also correlated to remodeling of the tumor microenvironment, which favors cancer cell progression. This study suggests expression of EZH2 in adult acinar cells restricts PDAC initiation and progression by affecting both the tumour microenvironment and acinar cell differentiation.

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EZH2 deletion does not impact acinar cell regeneration but restricts progression to pancreatic cancer in mice [RNA-seq]

2024-08-31 | GSE262767 | GEO

HDAC5-ChIP seq data in HDAC5-driven KRASG12D-independent PDAC cells

Project description:HDAC5-ChIP seq data in HDAC5-driven KRASG12D-independent PDAC cells

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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

Gene Expression Analysis of PDAC tumors

Project description:Analysis of myofibroblast ablation at the gene expression level of PDAC tumors. Total RNA optained from pancreas of PDAC mice with and without aSMA myofibroblast ablated In addition, late stage aSMA ablated mice were treated with anti-CTLA4 treatment

2015-01-20 | E-GEOD-52812 | biostudies-arrayexpress

RNA sequencing of organoids isolated from pancreatic cancer mouse model KRASG12D; p53R172H; Ptf1a-Cre.

Project description:We studied the transcriptomics of pancreatic ductal adenocarcinoma (PDAC) and the role of a splicing factor called SF3B1 in this context. We generated mice that will develop PDAC via an inducible expression of KRASG12D; p53R172H specifically in the pancreas using a Ptf1a-Cre.

2017-01-09 | GSE93279 | GEO

Nuclear protein (Nupr)-1 is required for pancreatic adenocarcinoma development in Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl mice

Project description:Nuclear Protein 1 (Nupr1) is a major actor of the cell stress response required for KrasG12D-driven formation of pancreatic intraepithelial neoplastic (PanINs) lesions in mice. We investigated the impact of Nupr1-depletion on the development and biology of murin pancreatic adenocarcinomas (PDAC) in the Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mice. We found that only one half of Nupr1-deficient mice developed PDAC. This is related to increased caspase 3 activity and low IER3 expression in Nupr1-deficient;KIC in the pancreas. Moreover, when Nupr1-deficient;KIC mice do develop PDAC, tumors present with impaired epithelial-to-mesenchymal transition (EMT). Transcriptoma analysis revealed that Nupr1-deficient and Nupr1wt;KIC PDACs presented enrichment of gene signatures of the human classical- and quasi-mesenchymal (QM)-PDAC respectively. Moreover, Nupr1-deficient;KIC PDACs shared with human classical-PDACs overexpression of Kras-activation genes. In addition, cells derived from Nupr1-deficient;KIC PDACs formed fewer microspheres in vitro compared to Nupr1wt;KIC cells, indicative of stemness impairment in the absence of Nupr1. Finally, we found that Nupr1-deficient;KIC cells were more sensitive to some anticancer drugs than their Nupr1wt counterpart. Hence, this study establishes the pivotal role of Nupr1 in PDAC progression after PanIN and in PDAC EMT in vivo, with an impact in PDAC cell stemness. As a consequence, according to absence or presence of Nupr1, KIC mice develop tumors that phenocopy human classical- or QM-PDAC, respectively, thus becoming attractive models for preclinical drug trials. We investigated the impact of the homozygous deletion of the Nupr1 gene on pancreatic adenocarcinoma development and biology in the Pdx1-cre;LSL-KrasG12D;Ink4a/Arffl/fl (KIC) mouse model.

2012-12-16 | E-GEOD-42322 | biostudies-arrayexpress

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