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

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

PROVIDER: PRJNA643218 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR12118232_1.fastq.gz	Fastqsanger.gz
	SRR12118232_2.fastq.gz	Fastqsanger.gz
	SRR12118233_1.fastq.gz	Fastqsanger.gz
	SRR12118233_2.fastq.gz	Fastqsanger.gz
	SRR12118234_1.fastq.gz	Fastqsanger.gz

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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

A revised model of clonal evolution of intraductal papillary mucinous neoplasm-related pancreatic carcinogenesis

Project description:Similarity of DNA methylation profile observed in the multi-regions from the branch-off subtype intraductal papillary mucinous neoplasm-related pancreatic adenocarcinoma

2019-05-08 | GSE114163 | 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

Metabolic profiling of cyst fluid from patients with Intraductal Pancreatic Mucinous Neoplasm (part II)

Project description:The pancreatic cyst fluids were collected using a syringe aspiration of the cyst fluid immediately after surgical resection of the lesion. The cyst fluid were then aliquoted and stored in -80C freezer until ready to use. We plan on performing untargeted metabolomics analysis and unknown lipid analysis and identification on these pancreatic cyst fluid to find potential biomarkers that correlate with histopathological assessment and clinical behavior of these cystic lesions and thus to guide clinical management of patients. Abbreviations: IPMN - Intraductal Pancreatic Mucinous Neoplasm; MCN - mucinous cystic neoplasm; SCA - serous cystadenoma.

2017-07-14 | ST000823 | MetabolomicsWorkbench

Comprehensive Proteomic Characterization of Human Pancreatic Cyst Fluid from Intraductal Papillary Mucinous Neoplasm by LC-MS/MS

Project description:Intraductal papillary mucinous neoplasm (IPMN) is a duct-dilating precancerous lesion that grows in pancreatic ducts and is accompanied by the production of mucinous fluid. In recent years, its cystic fluid has been used molecularly for the differential diagnosis of other cystic tumors and malignancies. Thus, proteomic research of IPMN cyst fluid must be performed to identify an effective diagnostic biomarker. We examined the IPMN cyst fluid proteome using a novel proteomic strategy, combined with high-resolution LC-MS/MS. Although we did not deplete any high-abundance proteins, our dataset consistently detected thousands of proteins including pancreatic tumor markers, such as mucin family members, S100 proteins, and CEA-related proteins. In addition, we found 590 protein mutations through a variant sequence database search. Bioinformatics analyses were performed to determine biological functions and clinical meanings of canonical IPMN proteins and mutated proteins. Our proteomic platform and in-depth proteome dataset are valuable references that can be used in future studies.

2017-08-22 | PXD005671 | Pride

Quantitative Proteomic Analysis of Pancreatic Cyst Fluid Proteins Associated with Malignancy in Intraductal Papillary Mucinous Neoplasms

Project description:Intraductal papillary mucinous neoplasm (IPMN) is a benign tumor that grows within the pancreatic ducts characterized by the production of thick mucinous fluid by surrounding tumor cells. IPMN is the most important precursor lesion for pancreatic cancer that is the fourth most common cause of cancer deaths. Differentiating between low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive intraductal papillary mucinous neoplasms (IPMNs) remains a diagnostic challenge with current biomarkers, necessitating the development of novel biomarkers that can distinguish IPMN malignancy. We investigated differentially expressed proteins among pancreatic cyst fluids consisted of LGD, HGD, and invasive IPMN patients by using our novel proteomic strategy, and finally we discovered pancreatic cyst fluid protein marker candidates that can predict the malignant potential of IPMNs.

2018-05-01 | PXD008302 | Pride

GSK-3β inhibition promotes engraftment of ex vivo expanded hematopoietic stem cells

Project description:Glycogen synthase kinase-3β (GSK-3β) has been recently identified as an important regulator of stem cell function. In vitro studies show that GSK-3β inhibition delays proliferation of human haematopoietic progenitor cells while increasing numbers of late dividing multipotent progenitors. Gene expression analysis revealed that GSK-3β inhibition modulates the expression of a subset of genes that are transcriptional targets for cytokines. GSK-3β inhibition antagonised down-regulation of genes encoding cyclin dependent kinase inhibitor p57 and a member of the growth arrest and DNA damage 45 family, GADD45B as well as up-regulation of cyclin D1 by cytokines, providing a possible mechanism for the BIO-induced delay in cell cycle progression. Surprisingly, inhibition of GSK-3β earlier shown to prevent β-catenin degradation and promote the nuclear accumulation of β-catenin was not sufficient to activate its transcriptional targets in haematopoietic stem cells. GSK-3β inhibition up-regulated the expression of a several positive regulators of stem cell function suppressed during cytokine-induced proliferation. The data supports a clinical role for GSK-3β inhibition to improve engraftment efficiency of ex vivo expanded stem cells.

2010-03-26 | GSE21073 | GEO

A revised model of clonal evolution of intraductal papillary mucinous neoplasm-related pancreatic carcinogenesis

Project description:A revised model of clonal evolution of intraductal papillary mucinous neoplasm-related pancreatic carcinogenesis

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Quantitative Proteomic Profiling for Predicting Grade of Dysplasia in Intraductal Papillary Mucinous Neoplasm using Pancreatic Cyst Fluid

Project description:The increased number of pancreatic cyst lesions (PCLs) have been detected through the development of abdominal imaging techniques, such as computed tomography (CT), magnetic resonance imaging (MRI), and endoscopic ultrasound (EUS). However, accurate classification of cystic lesions is difficult because of the lack of standardized diagnostic methods, and thus potentially unnecessary surgical resection has been performed on pancreatic cyst patients. Among four most common types of cystic lesions of pancreas, intraductal papillary mucinous neoplasms (IPMNs), mucinous cystic neoplasms (MCN), serous cystic neoplasms (SCN), and solid pseudopapillary neoplasms (SPNs), IPMNs, the precursor lesion of pancreatic cancer, have been detected most frequently, and are subdivided into low-grade dysplasia (LGD), high-grade dysplasia (HGD), and invasive IPMN in accordance with their malignancy. To discover the potential biomarkers of the histological grades of IPMN, we investigated pancreatic cyst fluid proteins that are differentially expressed in accordance with the IPMN malignancy by LC-MS/MS analysis.

2020-09-06 | PXD016127 | Pride

Improved Detection of Circulating Epithelial Cells in Patients with Intraductal Papillary Mucinous Neoplasms

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