Comparative transcriptome analysis of Ptf1aCre;Kras,Brg1-/- vs. Ptf1a;Kras;p53+/- subcutaneous pancreatic ductal adenocarcinoma
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ABSTRACT:
ORGANISM(S): Mus musculus
PROVIDER: GSE52332 | GEO | 2013/11/14
SECONDARY ACCESSION(S): PRJNA227435
REPOSITORIES: GEO
Similar Datasets
Project description:In this experiment the RNA of s.c. grown tumors of cancer cell lines of murine Ptf1aCre;Kras,Brg1-/- vs. Ptf1a;Kras;p53+/- PDA was isolated and analyzed for gene expression. Ptf1aCre;Kras,Brg1-/- s.c. PDA grows more benign as compared to Ptf1a;Kras;p53+/- PDA; and the rationale of this study was to identify genes responsible for this different biological behavior. Total RNA of s.c. tumors of Ptf1aCre;Kras,Brg1-/- vs. Ptf1a;Kras;p53+/- cancer cell lines was isolated, purified and analyzed on the deep sequencing platform.
2013-11-14 | E-GEOD-52332 | biostudies-arrayexpress
Project description:Comparative transcriptome analysis of Ptf1aCre;Kras,Brg1-/- vs. Ptf1a;Kras;p53+/- subcutaneous pancreatic ductal adenocarcinoma
| PRJNA227435 | ENA
Project description:Brahma related gene 1 (BRG1), a catalytic ATPase subunit of SWI/SNF chromatin remodeling complexes, is silenced in approximately 10% of human pancreatic ductal adenocarcinomas (PDA). We previously showed that BRG1 inhibits the formation of intraductal pancreatic mucinous neoplasm (IPMN) and IPMN-derived PDA from ductal cells. However, the role of BRG1 in pancreatic intraepithelial neoplasia (PanIN) from acinar cells remains elusive. Here, we investigated the role of BRG1 in PanIN initiation and maintenance and its underlying mechanisms. Exclusive elimination of Brg1 in acinar cells of Ptf1a-CreER; KrasG12D; Brg1f/f (KBC) mice impaired the formation of acinar-to-ductal metaplasia (ADM) and PanIN independent of the presence of p53 mutation. We found that Sox9 expression was down-regulated in both Brg1-depleted acinar cell explants and BRG1-depleted ADMs/PanINs. Sox9 overexpression rescued this PanIN-attenuated phenotype in KBC mice. Furthermore, Brg1-deletion in established PanIN by using an inducible dual recombinase system resulted in regression of the lesions in mice. Finally, expression of BRG1 and SOX9 was also positively correlated in human PanIN-derived PDAs. In summary, BRG1 is critical for both initiation and maintenance of PanIN. Mechanistically, this is mediated through positive regulation of SOX9 expression. Thus, the BRG1/SOX9 axis is a potential target for the prevention of PanIN-derived PDA.
2018-01-01 | GSE93615 | GEO
Project description:Global mRNA expression profiles of murine primary PDAC cells following JQ1 or SAHA monotherapy as well as JQ1-SAHA combination therapy were collected using Affymetix mouse whole genome array (Mouse Genome 430A 2.0 Array) . Primary PDAC cells isolated from Ptf1aCre/+;Kras+/LSL-G12D;p53lox/lox (Kras;p53) mice were treated either with JQ1 (100 nM) or SAHA (2000 nM) or vehicle 10% (2-Hydroxypropyl)-β-cyclodextrin (Sigma-Aldrich) or as combination therapy with the indicated dosage for monotherapy. Total RNA isolation was performed after 6 hours of treatment. Primary PDAC cells from Ptf1aCre/+;Kras+/LSL-G12D;p53lox/lox (Kras;p53) mice treated either with JQ1, SAHA, vehicle or JQ1-SAHA combination were analyzed by global gene expression analysis.
2015-09-20 | E-GEOD-64836 | biostudies-arrayexpress
Project description:We have carried out transcriptional profile analysis in WT MICE and bitransgenic Pdx1-cre/Kras*A MICE baring Pancreatic Ductal Adenocarcinoma Mouse models faithfully simulating human cancer are valuable for genetic identification of potential drug-targets but, among them, the most advantageous for practical use in subsequent preclinical testing of candidate therapeutic regimes are those exhibiting rapid tumor development. Considering that a KRAS mutation (predominantly in codon 12, such as KRASG12D; KRAS*) occurs with high frequency (~90%) in cases of human pancreatic ductal adenocarcinoma (PDA)1, we sought to develop a mouse PDA model that would exhibit high tumor incidence and short latency by ectopic overexpression of Kras*. Five WT mice and 6 bitransgenic Pdx1-cre/Kras*A MICE baring Pancreatic Ductal Adenocarcinoma were used to identify key genes in the formation of panceatic malignacies
2014-09-01 | E-GEOD-53659 | biostudies-arrayexpress
Project description:Because Ptf1a is a transcription factor, this protein should regulate transcription of various genes in Ptf1a-expressing cells of the hypothalamus. To detect those downstream genes, we purified cells in the Ptf1a-lineage from the hypothalamus at E14.5 by FACS sorting, subsequently performed RNA-seq analysis and obtained 706 differentially expressed genes. 386 genes had lower and 320 had higher expression in Ptf1a-lineage cells from homozygous Ptf1a deficient mice. The down-regulated genes included Prdm13, Corl2 and Lhx5 that were known downstream targets of Ptf1a, in addition, Sox3 and Nkx2-1, which are known to be required for hypothalamic development. Interestingly, among those affected genes, we detected several genes encoding transmembrane and/or secreted proteins, such as Jag2 (ligand for Notch receptors), Sema6b, Sema4g (ligands for Plexin family proteins). These genes may have a non-cell autonomous role in the sexual differentiation of hypothalamic cells adjacent to Ptf1a-lineage cells. Kiss1 expression was not altered, as was expected by the finding that most Kiss1-expressing cells were not in the Ptf1a lineage.
2018-04-21 | GSE112935 | GEO
Project description:Pancreatic Ductal Adenocarcinoma (PDA) develops predominantly through pancreatic intraepithelial neoplasia (PanIN) and intraductal papillary mucinous neoplasm (IPMN) precursor lesions. Pancreatic acinar cells are reprogrammed to a “ductal like” state during PanIN-PDA formation. Here, we demonstrate a parallel mechanism operative in mature duct cells where they undergo “ductal retrogression” to form IPMN-PDA. Brg1, a catalytic subunit of the SWI/SNF complexes, plays a critical antagonistic role in IPMN-PDA development. In mature duct cells Brg1 inhibits the dedifferentiation that precedes neoplastic transformation, thus attenuating tumor initiation. In contrast, Brg1 promotes tumorigenesis in full-blown PDA by supporting a mesenchymal-like transcriptional landscape. We have exploited this duality of Brg1 functions to develop a novel therapeutic approach using an epigenetic drug JQ1. In summary, this study demonstrates the context-dependent roles of Brg1 and points to potential therapeutic treatment options based on epigenetic regulation in PDA. Duct cells were isolated from mice of 3 different genotypes and duct cells from 3 mice of each genotype were sequenced. For the put back experiments, control retrovirus and that expressing Brg1 were transdcued in Brg1 null IPMN mouse cell line.
2015-07-29 | E-GEOD-65315 | biostudies-arrayexpress
Project description:This experiment used RNA-Seq technology to explore gene expression in mouse Ptf1a^YFP/+ [het] FACS sorted cells at E11.5 (early pancreatic Multipotent Progenitor Cells) and E15.5 (nascent acinar cells) as well as in Ptf1a^YFP/YFP [null] at E11.5 (delayed early MPC). 376 selected genes identified as differentially expressed between early pancreatic MPC and nascent acinar cells or between early pancreatic and delayed early MPCs have then been examined by Taqman Low Density Arrays (TLDAs) with Real Time RT-PCR for each 1-day time point from E10.5 to E15. 5 in Ptf1a^YFP/+ [het] and for E10.5 and E11.5 in Ptf1aYFP/YFP [null] . Finally, 94 genes identified in the first phase of TLDAs (including 2 endogenous control, Gapdh and 18S) were analyzed in a second TLDA phase for each 1-day time point from E10.5 to -E18.5 in Ptf1a^YFP/+ [het] and for E11.5 in Ptf1aYFP/YFP [null] with biological replicates (n>=3) for each time point.
2014-11-15 | E-MTAB-449 | biostudies-arrayexpress
Project description:Oncogenic mutations in tumor cells regulate signaling both within tumor cells and heterotypic stromal cells. However, whether oncogenes regulate tumor cell signaling via stromal cells is poorly understood. Here we show that oncogenic KRAS (KRAS-G12D) uniquely regulates tumor cell signaling via stromal cells. By combining cell-specific proteome labeling with phosphoproteomic multiplexing we conducted a multivariate analysis of heterocellular KRAS-G12D signaling in Pancreatic Ductal Adenocarcinoma (PDA) cells. By engaging heterotypic fibroblasts, KRAS-G12D drives unique reciprocal signaling in tumor cells to employ additional kinases and double the number of regulated signaling nodes from cell-autonomous KRAS-G12D. Heterocellular signaling produces a distinct tumor cell phosphoproteome, total proteome, and increase mitochondria capacity via an IGF1R/AXL-AKT axis. Reciprocal KRAS-G12D phenotypes require a heterocellular context and are unreachable by cell-autonomous KRAS-G12D alone. These results demonstrate oncogene signaling should be viewed as a heterocellular process and our existing homocellular perspective underrepresents the extent of oncogene signaling in cancer.
2016-04-19 | PXD003223 | Pride
Project description:Mutations of subunit genes of the SWI/SNF chromatin remodeling complexes were found in 12-23% of human Pancreatic Ductal Adenocarcinoma (PDAC). We previously showed that Brg1, a catalytic ATPase subunit of the SWI/SNF chromatin remodeling complexes, inhibits the formation of intraductal pancreatic mucinous neoplasms (IPMN) and IPMN-derived PDAC from ductal cells. On the other hand, ARID1A is the most frequent target of mutations in the SWI/SNF chromatin remodeling complexes in human PDAC. We found that Arid1a loss in the context of mutant Kras resulted in formation of IPMN and PDAC. We also found that the incidence of PDAC formation in Ptf1a-Cre; KrasG12D; Arid1af/f mice was markedly lower than that in Ptf1a-Cre; KrasG12D; Brg1f/f mice despite the similarities between Arid1a-deficient and Brg1-deficient IPMNs. We extracted total RNA from intraductal papillary mucinous neoplasms (IPMNs) in Ptf1a-Cre; KrasG12D; Arid1af/f and Ptf1a-Cre; KrasG12D; Brg1f/f mice and perform microarray analysis.
2018-03-31 | GSE96926 | GEO