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

ABSTRACT: 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.

ORGANISM(S): Mus musculus

PROVIDER: GSE65315 | GEO | 2015/07/29

SECONDARY ACCESSION(S): PRJNA273664

REPOSITORIES: GEO

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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.

2015-07-29 | E-GEOD-65315 | biostudies-arrayexpress

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.

2018-01-01 | GSE93615 | GEO

Nuclear GSK-3β and Oncogenic KRas Promote Expansion of Terminal Duct Cells and the Development of Intraductal Papillary Mucinous Neoplasm

Project description:Intraductal papillary mucinous neoplasm (IPMN) represents one precursor lesion of pancreatic ductal adenocarcinoma (PDA), but the cell-of-origin remains unclear. Here we describe a new mouse model in which pancreas-specific Cre activation of a nuclear glycogen synthase kinase-3β transgene is combined with oncogenic KRas (referred to as KNGC). KNGC mice show accumulation of neoplastic ductal cells at 4-weeks that progressively develop into IPMN with low-grade dysplasia in advanced age. RNA-sequencing identified expression of several genes found in the terminal duct cell lineage including Agr2 and Aqp5. Interestingly, Aqp5, a water channel, was found to be required for the development of IPMN lesions in KNGC mice. Staining of human IPMN samples indicates that these preneoplastic lesions also arise from expansion of the terminal duct population. Altogether, these data highlight the utility of the KNGC model for understanding the biology of IPMN and potential utility in defining predictive biomarkers of IPMN – PDA development.

2022-03-22 | GSE153548 | GEO

Nuclear GSK-3β and Oncogenic KRas Promote Aqp5+ Pancreatic Duct Stem Cell Expansion

Project description:Intraductal papillary mucinous neoplasm (IPMN) represents the most commonly diagnosed precursor lesion of pancreatic ductal adenocarcinoma (PDA), however the cell-of-origin remains unclear. Herein, we show that pancreas-specific activation in mice of nuclear-targeted glycogen synthase kinase-3β and oncogenic KRasG12D leads to the loss of acinar cells, the expansion of ductal cells, and the rapid development of IPMN with low-grade dysplasia. RNA-sequencing identified the expression of several ductal stem cell lineage genes including the water channel AQP5. The Aqp5+ pancreatic ductal cell pool was proliferative, phenotypically distinct from mature pancreatic ductal cells, and deletion of AQP5 limited IPMN development. Significantly, Aqp5 is highly expressed in human IPMN along with GSK-3b suggesting that human preneoplastic lesions likely arise from the expansion of an Aqp5+ pancreatic ductal stem cell. Altogether, these data identify Aqp5+ ductal cells in the mouse and human pancreas as the likely cell-of-origin for IPMN.

2022-03-22 | GSE169618 | GEO

Kinase activities in pancreatic ductal adenocarcinoma with prognostic and therapeutic avenues

Project description:The aim of this experiment is to unravel PDAC biology and phospho-print based on aberrant kinase activities and proteome alterations. For this we will perform pTYyrIP, Bravo_IMAC, and protein expression data of n=56 tissues encompassing 47 pancreatic ductal adenocarcinoma (PDAC), 5 cholangiocarcinoma, 1 Intraductal Papillary Mucinous Neoplasm (IPMN), 1 pancreatitis and 1 pancreatitis-Pancreatic Intraepithelial Neoplasia (PanIN) tissue. Pancreatitis, PanIN, and IPMN are seen as early events predecessing PDAC. An equiproportional pool of 5 PDAC cell lines (PANC1, SUIT-2, CFPAC-1, HPAC, MIAPACA2) is also taken along.

2024-04-23 | PXD043111 | Pride

Transcriptome analysis of Arid1a-deficient IPMN and Brg1-deficient IPMN

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

Next generation sequencing facilitates promoter-level analysis of pancreatic cancer cell lines transcriptomes

Project description:Both pancreatic intraepithelial neoplasia (PanIN), a frequent precursor of pancreatic cancer, and intraductal papillary mucinous neoplasm (IPMN), a less common precursor, undergo several phases of molecular conversions and finally develop into highly malignant solid tumors with negative effects on the quality of life. We approached this long-standing issue by examining the following PanIN/IPMN cell lines derived from mouse models of pancreatic cancer: Ptf1a–Cre; KrasG12D; p53f/+ and Ptf1a–Cre; KrasG12D; Brg1f/f PDAs. The mRNA from these cells was subjected to a cap analysis of gene expression (CAGE) to map the transcription starting sites and quantify the expression of promoters across the genome.

2019-11-13 | GSE139648 | GEO

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

A Central Role for RAF-MEK-ERK Signaling in the Genesis and Maintenance of Pancreatic Ductal Adenocarcinoma.

Project description:Although KRAS mutation is a hallmark of pancreatic ductal adenocarcinoma (PDA), mutated KRAS remains an intractable pharmacological target. Consequently, an understanding of the RAS effector pathway(s) required for PDA maintenance is critical for improved strategies to treat this disease. Here we demonstrate that expression of BRAFV600E, but not PIK3CAH1047R, in the mouse pancreas led to PanIn lesions. Moreover, concomitant expression of BRAFV600E and TP53R270H resulted in lethal PDA. A large panel of PDA cell line panel was deployed to derive genomic classifiers of MEK inhibitor sensitivity. This classifier correctly predicted survival benefit in two novel in vivo syngeneic, orthotopic models of PDA. Consequently, we conclude that RAF?MEK?ERK signaling is central to the initiation, progression and maintenance of PDA and propose predictive biomarkers of response to MEK inhibition. These data further emphasize the value of leveraging multiple experimental systems to prioritize pathways for intervention in human PDA. RNA was extracted from human PDA cell line samples and hybridized on Affymetrix U133 plus 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA. RNA was extracted from mouse PDA cell lines and hybridized on Affymetrix Mouse 430a 2.0 microarrays. The CEL files were processed using R based Bioconductor and normalized values were obtained using RMA.

2012-07-09 | E-GEOD-30562 | biostudies-arrayexpress

miRNA expression profiles in Pancreatic Cystic tumours and Pancreatic Cancer

Project description:MicroRNA (miRNA) expression profiles have been described in pancreatic ductal adenocarcinoma (PDAC), but these have not been compared with premalignant lesions. We wished to identify miRNA expression profiles in pancreatic cystic tumors with low malignant potential (serous microcystic adenomas) and high malignant potential (mucinous cystadenoma and intraductal papillary mucinous neoplasm (IPMN)) and compare these to PDAC and carcinoma-ex-IPMN (CEI). n= 20 samples Benign Pancreatic Cystic Tumour (n=7 Microcystic, n= 6 Mucinous, n= 7 IPMN) were compared with n= 9 samples of carcinoma ex IPMN and n= 14 samples of pancreatic cancer (adenocarcinoma) for known homo sapiens miRNAs (mirbase 13).

2011-05-18 | E-GEOD-29352 | biostudies-arrayexpress

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