Project description:To further development of our lncRNA and mRNA expression approach to pancreatic ductal adenocarcinoma(PDAC), we have employed lncRNA and mRNA microarray expression profiling as a discovery platform to identify lncRNA and mRNA expression in pancreatic ductal adenocarcinoma.Human pancreatic ductal adenocarcinoma tissues and normal pancreatic tissues from PDAC donors and other duodenum diseases donors. analyze mRNA and lncRNA expression in pancreatic ductal adenocarcinoma (PDAC) by microarray platform
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
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.
Project description:Pancreatic ductal adenocarcinoma, caused by activating mutation in K-Ras, is an aggressive malignancy due to its early invasion and matastasis. Ral GTPases, negatively regulated by RalGAP, are activated downstream of Ras and play a crucial role in development and progression of pancreatic ductal adenocarcinoma. However, the underlying mechanisms remain unclear. We used microarrays to detail the global programme of gene expression underlying the human pancreatic ductal adenocarcinoma cell line, MIA PaCa-2 with RalGAPβ deficiency or not, and identified distinct classes of Ral activation-related mRNA.
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.
Project description:Pancreatic acinar cells can dedifferentiate upon tissue injury and acquire ductal characteristics. This acquisition of duct cell features is critical in tumor development. Nevertheless, duct cells themselves are less prone for development of PDAC (pancreatic ductal adenocarcinoma) than dedifferentiated acini. We aimed to clarify which genes are unique for dedifferentiated acini. Mixed exocrine preparations of acinar and duct cells were obtained from human pancreatic donor organs and cultured to induce dedifferentiation. We lineage-labeled and FACS-purified these human dedifferentiated acinar cells and compared them to duct cells from the same donor (n=5).
Project description:Pancreatic cancer is a heterogeneous disease and consists of distinct subtypes. Here, we investigated candidate suppressor genes of the basal-like/squamous subtype, a more aggressive molecular subtype of pancreatic ductal adenocarcinoma (PDAC). Through an integrated transcriptome analysis, we identified the ADRA2A, as being downregulated in the basal-like/squamous PDAC using a discovery and validation approach. ADRA2A downregulation is associated with decreased patient survival. The goal of this study was to identify ADRA2A-induced molecular signatures in PDAC.
Project description:To further development of our lncRNA and mRNA expression approach to pancreatic ductal adenocarcinoma(PDAC), we have employed lncRNA and mRNA microarray expression profiling as a discovery platform to identify lncRNA and mRNA expression in pancreatic ductal adenocarcinoma.Human pancreatic ductal adenocarcinoma tissues and normal pancreatic tissues from PDAC donors and other duodenum diseases donors.
