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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE148335 | GEO | 2021/12/31

REPOSITORIES: GEO

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

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

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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

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

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

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

TGIF1 loss contributes to progression of KRASG12D-induced pancreatic ductal adenocarcinoma involving HAS2-CD44 activation and PD-L1 upregulation.

Project description:Transcriptional profiling of mouse Pancreatic cancer cells comparing Pdx1-Cre LSL-KrasG12D TGIF1L/L P53L/L cells with Pdx1-Cre LSL-KrasG12D P53L/L cells, and to determine the effects of TGIF1 deletion on PDAC gene expression.

2018-01-22 | GSE108843 | GEO

RNA-seq of sorted KPC Sf3b1-K700E murine PDAC cells

Project description:We established a mouse model of KrasG12D, Trp53-/- and Sf3b1-K700E murine pancreatic cancer to elucidate the impact of the SF3B1 mutation found in human PDAC on the KPC mouse model.

2022-06-07 | GSE203339 | GEO

Pten deficiency cooperates with KrasG12D to activate NFkB pathway promoting the development of malignant pancreatic ductal adenocarcinoma

Project description:Almost all human pancreatic ductal adenocarcinomas (PDACs) are driven by oncogenic Kras and the progression of the disease is characterized by the serial appearance of certain genetic lesions. Mouse models have convincingly shown that Kras mutation induces classical PanIN lesions that can progress to PDAC in the appropriate tumor suppressor background. However, the cooperative mechanism between mutant Kras-dependent signaling surrogates and other oncogenic pathways remains to be fully elucidated in order to devise better therapeutic strategy. Mounting evidence PTEN/PI3K perturbation on PDAC tumorigenesis, we observed frequent PTEN inactivation at both genomic and histopathological levels in primary human PDAC samples. The importance of PTEN/PI3K pathway during the development of PDAC was further supported by genetic studies demonstrating that Pten deficiency in cooperation with Kras activation accelerated the formation of invasive PDAC. Mechanistically, combined Kras mutation and Pten inactivation leads to NFkB activation and subsequent induction of cytokine pathways, accompanied with strong stromal activation and immune cell infiltration. Therefore, PTEN/PI3K pathway dictates the activity of NFkB network and serves as a major surrogate during Kras-mediated pancreatic tumorigenesis. Primary pancreatic ductal epithelial cell cultures were established from 6 week old Pdx1-Cre;LSL-KrasG12D L/+ (n=3) or Pdx1-Cre;LSL-KrasG12D L/+;Pten L/+ (n=5) mice. Total RNA was collected from early passage cells.

2011-08-31 | E-GEOD-25828 | biostudies-arrayexpress

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