Document Detail


Identification of Sox9-dependent acinar-to-ductal reprogramming as the principal mechanism for initiation of pancreatic ductal adenocarcinoma.
MedLine Citation:
PMID:  23201164     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
Tumors are largely classified by histologic appearance, yet morphologic features do not necessarily predict cellular origin. To determine the origin of pancreatic ductal adenocarcinoma (PDA), we labeled and traced pancreatic cell populations after induction of a PDA-initiating Kras mutation. Our studies reveal that ductal and stem-like centroacinar cells are surprisingly refractory to oncogenic transformation, whereas acinar cells readily form PDA precursor lesions with ductal features. We show that formation of acinar-derived premalignant lesions depends on ectopic induction of the ductal gene Sox9. Moreover, when concomitantly expressed with oncogenic Kras, Sox9 accelerates formation of premalignant lesions. These results provide insight into the cellular origin of PDA and suggest that its precursors arise via induction of a duct-like state in acinar cells.
Authors:
Janel L Kopp; Guido von Figura; Erin Mayes; Fen-Fen Liu; Claire L Dubois; John P Morris; Fong Cheng Pan; Haruhiko Akiyama; Christopher V E Wright; Kristin Jensen; Matthias Hebrok; Maike Sander
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-11-29
Journal Detail:
Title:  Cancer cell     Volume:  22     ISSN:  1878-3686     ISO Abbreviation:  Cancer Cell     Publication Date:  2012 Dec 
Date Detail:
Created Date:  2012-12-14     Completed Date:  2013-04-22     Revised Date:  2013-12-17    
Medline Journal Info:
Nlm Unique ID:  101130617     Medline TA:  Cancer Cell     Country:  United States    
Other Details:
Languages:  eng     Pagination:  737-50     Citation Subset:  IM    
Copyright Information:
Copyright © 2012 Elsevier Inc. All rights reserved.
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MeSH Terms
Descriptor/Qualifier:
Acinar Cells / metabolism,  pathology*
Carcinoma, Pancreatic Ductal / genetics,  metabolism,  pathology*
Genes, ras
Humans
Metaplasia
Mutation
Pancreatic Neoplasms / genetics,  metabolism,  pathology*
Precancerous Conditions / genetics*,  metabolism,  pathology
SOX9 Transcription Factor / genetics*,  metabolism
Grant Support
ID/Acronym/Agency:
DP2 OD002420-01/OD/NIH HHS; P30 CA23100/CA/NCI NIH HHS; P30 DK063720/DK/NIDDK NIH HHS; R01 CA112537/CA/NCI NIH HHS; R01 DK078803/DK/NIDDK NIH HHS; T32CA121938/CA/NCI NIH HHS
Chemical
Reg. No./Substance:
0/SOX9 Transcription Factor; 0/SOX9 protein, human; 0/Sox9 protein, mouse
Comments/Corrections
Comment In:
Cancer Cell. 2012 Dec 11;22(6):701-3   [PMID:  23238009 ]
Gastroenterology. 2013 Oct;145(4):904-7   [PMID:  23973677 ]

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