Acinar cells contribute to the molecular heterogeneity of pancreatic intraepithelial neoplasia.
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 Kras(G12D) expression, we took advantage of LSL-Kras(G12D/+)/p48(Cre/+) 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 acinar-ductal metaplasia follow similar molecular pathways. Indeed, immunofluorescence studies confirmed the presence of acinar cells within mPanIN lesions, raising the possibility that Kras(G12D)-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.
Zhu
Liqin
L
Department of Biological Sciences and the Purdue Cancer Center, Purdue University, Hansen Life Sciences Research Building, West Lafayette, IN 47907-2064, USA.
Shi
Guanglu
G
Schmidt
C Max
CM
Hruban
Ralph H
RH
Konieczny
Stephen F
SF
D000230:Adenocarcinoma / Q000235:genetics / Q000473:pathology; D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000473:pathology*; D002352:Carrier Proteins / Q000378:metabolism; D019070:Cell Lineage; D004847:Epithelial Cells; D011905:Genes, ras; D018740:Genetic Heterogeneity; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit / Q000235:genetics; D047908:Intracellular Signaling Peptides and Proteins; D008679:Metaplasia / Q000235:genetics / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009154:Mutation; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D011230:Precancerous Conditions / Q000235:genetics* / Q000473:pathology; D000090063:Proto-Oncogene Mas; D051880:Receptors, Notch / Q000235:genetics
D002352:Carrier Proteins; C498804:Erbb2ip protein, mouse; D050834:Interferon-Stimulated Gene Factor 3, gamma Subunit; D047908:Intracellular Signaling Peptides and Proteins; C494228:Isgf3g protein, mouse; C000715470:MAS1 protein, human; D000090063:Proto-Oncogene Mas; D051880:Receptors, Notch