Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia

Liqin Zhu, Guanglu Shi, C. Schmidt, Ralph H. Hruban, Stephen F. Konieczny

Research output: Contribution to journalArticle

142 Citations (Scopus)

Abstract

A number of studies have shown that pancreatic ductal adenocarcinoma develops through precursor lesions termed pancreatic intraepithelial neoplasia (PanIN). PanINs are thought to initiate in the small ducts of the pancreas through activating mutations in the KRAS proto-oncogene. What remains unanswered is the identification of the individual cell type(s) that contributes to pancreatic ductal adenocarcinoma formation. To follow the cellular and molecular changes that occur in acinar and duct cell properties on KrasG12D expression, we took advantage of LSL-KrasG12D/+/p48Cre/+ mice, which faithfully mimic the human disease. In young animals (4 weeks), the predominant cellular alteration in the exocrine pancreas was acinar metaplasia in which individual acini consisted of acinar cells and duct-like cells. Metaplastic acinar structures were highly proliferative, expressed Notch target genes, and exhibited mosaic expression patterns for epidermal growth factor receptor, ErbB2, and pErk. This expression pattern paralleled the expression pattern detected in mouse PanINs, suggesting that mouse PanINs and acinarductal metaplasia follow similar molecular pathways. Indeed, immunofluorescence studies confirmed the presence of acinar cells within mPanIN lesions, raising the possibility that KrasG12D-induced mPanINs develop from acinar cells that undergo acinar-ductal metaplasia. Identification of an acinar contribution to PanIN formation offers new directions for successful targeted therapeutic approaches to combat this disease.

Original languageEnglish
Pages (from-to)263-273
Number of pages11
JournalAmerican Journal of Pathology
Volume171
Issue number1
DOIs
StatePublished - Jul 2007

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Acinar Cells
Metaplasia
Neoplasms
Adenocarcinoma
Exocrine Pancreas
Proto-Oncogenes
Epidermal Growth Factor Receptor
Fluorescent Antibody Technique
Pancreas
Mutation
Genes
Therapeutics

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Cite this

Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. / Zhu, Liqin; Shi, Guanglu; Schmidt, C.; Hruban, Ralph H.; Konieczny, Stephen F.

In: American Journal of Pathology, Vol. 171, No. 1, 07.2007, p. 263-273.

Research output: Contribution to journalArticle

Zhu, Liqin ; Shi, Guanglu ; Schmidt, C. ; Hruban, Ralph H. ; Konieczny, Stephen F. / Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia. In: American Journal of Pathology. 2007 ; Vol. 171, No. 1. pp. 263-273.
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