Dataset Information

Atypical flat lesions derive from pancreatic acinar cells.

ABSTRACT:

Objectives

Pancreatic ductal adenocarcinoma (PDAC) is thought to derive from different precursor lesions including the recently identified atypical flat lesions (AFL). While all precursor lesions and PDAC share ductal characteristics, there is an ongoing debate about the cellular origin of the different PDAC precursor lesions. In particular, pancreatic acinar cells have previously been shown to display a remarkable plasticity being able to undergo ductal dedifferentiation in the context of oncogenic stimuli.

Methods

Histological analyses were performed in a murine PDAC model that specifically expresses oncogenic Kras in adult pancreatic acinar cells. Occurrence, characterization, and lineage tracing of AFLs were investigated.

Results

Upon expression of oncogenic Kras in adult pancreatic acinar cells, AFLs with typical morphology and expression profile arise. Lineage tracing confirmed that the AFLs were of acinar origin.

Conclusions

Using a murine PDAC model, this study identifies pancreatic acinar cells as a cellular source for AFLs.

SUBMITTER: von Figura G

PROVIDER: S-EPMC5770228 | biostudies-literature | 2017 May - Jun

REPOSITORIES: biostudies-literature

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Atypical flat lesions derive from pancreatic acinar cells.

von Figura Guido G Fahrenkrog-Petersen Leonie L Hidalgo-Sastre Ana A Hartmann Daniel D Hüser Norbert N Schmid Roland M RM Hebrok Matthias M Roy Nilotpal N Esposito Irene I

Pancreatology : official journal of the International Association of Pancreatology (IAP) ... [et al.] 20170425 3

<h4>Objectives</h4>Pancreatic ductal adenocarcinoma (PDAC) is thought to derive from different precursor lesions including the recently identified atypical flat lesions (AFL). While all precursor lesions and PDAC share ductal characteristics, there is an ongoing debate about the cellular origin of the different PDAC precursor lesions. In particular, pancreatic acinar cells have previously been shown to display a remarkable plasticity being able to undergo ductal dedifferentiation in the context ...[more]

PMID: 28473229

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Project description:The pancreatic β cells can synthesize dopamine by taking L-dihydroxyphenylalanine, but whether pancreatic acinar cells synthesize dopamine has not been confirmed. By means of immunofluorescence, the tyrosine hydroxylase -immunoreactivity and aromatic amino acid decarboxylase (AADC)- immunoreactivity were respectively observed in pancreatic acinar cells and islet β cells. Treatment with L-dihydroxyphenylalanine, not tyrosine, caused the production of dopamine in the incubation of INS-1 cells (rat islet β cell line) and primary isolated islets, which was blocked by AADC inhibitor NSD-1015. However, only L-dihydroxyphenylalanine, but not dopamine, was detected when AR42J cells (rat pancreatic acinar cell line) were treated with tyrosine, which was blocked by tyrosine hydroxylase inhibitor AMPT. Dopamine was detected in the coculture of INS-1 cells with AR42J cells after treatment with tyrosine. In an in vivo study, pancreatic juice contained high levels of L-dihydroxyphenylalanine and dopamine. Both L-dihydroxyphenylalanine and dopamine accompanied with pancreatic enzymes and insulin in the pancreatic juice were all significantly increased after intraperitoneal injection of bethanechol chloride and their increases were all blocked by atropine. Inhibiting TH with AMPT blocked bethanechol chloride-induced increases in L-dihydroxyphenylalanine and dopamine, while inhibiting AADC with NSD-1015 only blocked the dopamine increase. Bilateral subdiaphragmatic vagotomy of rats leads to significant decreases of L-dihydroxyphenylalanine and dopamine in pancreatic juice. These results suggested that pancreatic acinar cells could utilize tyrosine to synthesize L-dihydroxyphenylalanine, not dopamine. Islet β cells only used L-dihydroxyphenylalanine, not tyrosine, to synthesize dopamine. Both L-dihydroxyphenylalanine and dopamine were respectively released into the pancreatic duct, which was regulated by the vagal cholinergic pathway. The present study provides important evidences for the source of L-dihydroxyphenylalanine and dopamine in the pancreas.

Project description:Background and aimsDevelopment of pancreatic ductal adenocarcinoma (PDAC) is a multistep process intensively studied; however, precocious diagnosis and effective therapy still remain unsatisfactory. The role for Notch signaling in PDAC has been discussed controversially, as both cancer-promoting and cancer-antagonizing functions have been described. Thus, an improved understanding of the underlying molecular mechanisms is necessary. Here, we focused on RBPJ, the receiving transcription factor in the Notch pathway, examined its expression pattern in PDAC, and characterized its function in mouse models of pancreatic cancer development and in the regeneration process after acute pancreatitis.MethodsConditional transgenic mouse models were used for functional analysis of RBPJ in the adult pancreas, initiation of PDAC precursor lesions, and pancreatic regeneration. Pancreata and primary acinar cells were tested for acinar-to-ductal metaplasia together with immunohistology and comprehensive transcriptional profiling by RNA sequencing.ResultsWe identified reduced RBPJ expression in a subset of human PDAC specimens. Ptf1α-CreERT-driven depletion of RBPJ in transgenic mice revealed that its function is dispensable for the homeostasis and maintenance of adult acinar cells. However, primary RBPJ-deficient acinar cells underwent acinar-to-ductal differentiation in ex vivo. Importantly, oncogenic KRAS expression in the context of RBPJ deficiency facilitated the development of pancreatic intraepithelial neoplasia lesions with massive fibrotic stroma formation. Interestingly, RNA-sequencing data revealed a transcriptional profile associated with the cytokine/chemokine and extracellular matrix changes. In addition, lack of RBPJ delays the course of acute pancreatitis and critically impairs it in the context of KRASG12D expression.ConclusionsOur findings imply that downregulation of RBPJ in PDAC patients derepresses Notch targets and promotes KRAS-mediated pancreatic acinar cells transformation and desmoplasia development.

Dataset Information

Atypical flat lesions derive from pancreatic acinar cells.

Objectives

Methods

Results

Conclusions

Publications

Atypical flat lesions derive from pancreatic acinar cells.

Similar Datasets

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