title: Inactivation of Smad4 accelerates Kras(G12D)-mediated pancreatic neoplasia.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is one of the most fatal human malignancies, with an overall 5-year survival rate of <5%. Genetic analysis of PDAC patient samples has shown that specific disease-associated mutations are correlated with histologically defined stages of neoplastic progression in the ductal epithelium. Activating mutations in KRAS are almost uniformly present in early-stage disease, with subsequent inactivating mutations in p16(INK4A), p53, and SMAD4 occurring in more advanced lesions. In this study, we have tested whether the loss of Smad4 would cooperate with an activating Kras(G12D) mutation to promote progression to PDAC using the Pdx1-Cre transgenic system to activate Kras(G12D) and delete Smad4 in all pancreatic lineages including the ductal epithelium. Analysis of double-mutant mice showed that loss of Smad4 significantly accelerated the progression of pancreatic intraepithelial neoplasias (mPanIN) and promoted a high incidence of intraductal papillary mucinous neoplasia and active fibrosis compared with Pdx1-Cre;Kras(G12D) or Pdx1-Cre;Smad4(lox/lox) mice. Occasionally, double-mutant mice progressed to locally invasive PDAC with little evidence of metastases by 6 months of age and without the detectable loss of p53 or p16(Ink4A) expression or function. The loss of Smad4 only seemed to promote disease progression in the presence of the activated Kras(G12D) allele because we observed no abnormal pathology within the pancreata of 23 Pdx1-Cre;Smad4(lox/lox) animals that were analyzed up to 8 months of age. This indicates that Smad4 is dispensable for normal pancreatic development but is critical for at least partial suppression of multiple Kras(G12D)-dependent disease-associated phenotypes.
authors.affiliation: Department of Microbiology, The University of Alabama at Birmingham, Birmingham, AL 35294, USA.
authors.forename: Kyoko
authors.initials: K
authors.lastname: Kojima
authors.forename: Selwyn M
authors.initials: SM
authors.lastname: Vickers
authors.forename: N Volkan
authors.initials: NV
authors.lastname: Adsay
authors.forename: Nirag C
authors.initials: NC
authors.lastname: Jhala
authors.forename: Hyung-Gyoon
authors.initials: HG
authors.lastname: Kim
authors.forename: Trenton R
authors.initials: TR
authors.lastname: Schoeb
authors.forename: William E
authors.initials: WE
authors.lastname: Grizzle
authors.forename: Christopher A
authors.initials: CA
authors.lastname: Klug
mesh_terms: D000818:Animals; D002278:Carcinoma in Situ / Q000235:genetics* / Q000473:pathology; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology; D045744:Cell Line, Tumor; D004108:Dilatation, Pathologic / Q000235:genetics / Q000473:pathology; D018450:Disease Progression; D011905:Genes, ras; D051379:Mice; D008810:Mice, Inbred C57BL; D008813:Mice, Inbred ICR; D008822:Mice, Transgenic; D050505:Mutant Proteins / Q000235:genetics; D009362:Neoplasm Metastasis; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000473:pathology; D050500:Pancreatitis, Chronic / Q000235:genetics / Q000473:pathology; D051901:Smad4 Protein / Q000235:genetics* / Q000502:physiology