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PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance [ChIP-seq batch3]

ABSTRACT: Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA) making developmental regulators therapeutically attractive. Here, we demonstrate diverse functions for PDX1, a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of PanIN-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing EMT and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

ORGANISM(S): Mus musculus

PROVIDER: GSE91055 | GEO | 2017/11/27

SECONDARY ACCESSION(S): PRJNA356753

REPOSITORIES: GEO

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PDX1 dynamically regulates pancreatic ductal adenocarcinoma initiation and maintenance

Project description:Aberrant activation of embryonic signaling pathways is frequent in pancreatic ductal adenocarcinoma (PDA) making developmental regulators therapeutically attractive. Here, we demonstrate diverse functions for PDX1, a transcription factor indispensable for pancreas development, in the progression from normal exocrine cells to metastatic PDA. We identify a critical role for PDX1 in maintaining acinar cell identity, thus resisting the formation of PanIN-derived PDA. Upon neoplastic transformation, the role of PDX1 changes from tumor suppressive to oncogenic. Interestingly, subsets of malignant cells lose PDX1 expression while undergoing EMT and PDX1 loss is associated with poor outcome. This stage-specific functionality arises from profound shifts in PDX1 chromatin occupancy from acinar cells to PDA. In summary, we report distinct roles of PDX1 at different stages of PDA, suggesting that therapeutic approaches against this potential target need to account for its changing functions at different stages of carcinogenesis. These findings provide insight into the complexity of PDA pathogenesis and advocate a rigorous investigation of therapeutically tractable targets at distinct phases of PDA development and progression.

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Expression profiles of Brg1-depleted acinar cells during ductal conversion

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.

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Brg1 promotes both tumor suppressive and oncogenic activities at distinct stages of Pancreatic cancer formation

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.

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2019-12-06 | GSE90950 | GEO

Brg1 promotes both tumor suppressive and oncogenic activities at distinct stages of Pancreatic cancer formation

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Expression data from WT mice and bitransgenic Pdx1-cre/Kras*A mice bearing Pancreatic Ductal Adenocarcinoma

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

Expression profiles of Nrdc-depleted pancreas

Project description:Pancreatic ductal adenocarcinoma (PDA) is the devastating disease in urgent need to identify new strategies for diagnosing and treating. Chronic pancreatitis is a risk factor for PDA in humans. Nardilysin (Nrdc, NRDC), a zinc peptidase of the M16 family has been shown to promote cancer cell growth in vitro. Here, we report that pancreatic deletion of Nrdc dramatically accelerates formation of pancreatic intraepithelial neoplasia (PanIN) and invasive PDA in the presence of oncogenic Kras. Nrdc was expressed in the nucleus of pancreatic acinar cells and pancreatic deletion of Nrdc was dispensable for pancreatic development in mice, but led to spontaneous chronic pancreatitis concomitant with acinar-to-ductal conversion, fibrotic change, infiltrated inflammatory cells, increased apoptosis, and atrophic pancreas in adult mice. Ex vivo acinar cell explants culture experiments showed that acinar-to-ductal conversion was not induced through a cell autonomous mechanism and that expression of several chemokines, including Cxcl10, was markedly up-regulated in Nrdc-null pancreatic acinar cells. Microarray analysis revealed that pathways implicated in pancreatitis and tumorigenesis, including chemotaxis, NF-κB and Erk1/2 signaling, were up-regulated in Nrdc-cKO pancreata compared with WT controls. Finally, immunostaining for NRDC revealed absence of NRDC expression in a subset of human PanINs and PDAs. These data demonstrate a previously unappreciated tumor suppressive function of Nrdc in the pancreas through suppressing chronic pancreatitis with acinar-to-ductal conversion in mice.

2017-05-31 | GSE99438 | GEO

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