title: Loss of Activin Receptor Type 1B Accelerates Development of Intraductal Papillary Mucinous Neoplasms in Mice With Activated KRAS.
abstract: OBJECTIVE
  Activin, a member of the transforming growth factor-β (TGFB) family, might be involved in pancreatic tumorigenesis, similar to other members of the TGFB family. Human pancreatic ductal adenocarcinomas contain somatic mutations in the activin A receptor type IB (ACVR1B) gene, indicating that ACVR1B could be a suppressor of pancreatic tumorigenesis.
  
  
  METHODS
  We disrupted Acvr1b specifically in pancreata of mice (Acvr1b(flox/flox);Pdx1-Cre mice) and crossed them with LSL-KRAS(G12D) mice, which express an activated form of KRAS and develop spontaneous pancreatic tumors. The resulting Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice were monitored; pancreatic tissues were collected and analyzed by histology and immunohistochemical analyses. We also analyzed p16(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice and Cre-negative littermates (controls). Genomic DNA, total RNA, and protein were isolated from mouse tissues and primary pancreatic tumor cell lines and analyzed by reverse-transcription polymerase chain reaction, sequencing, and immunoblot analyses. Human intraductal papillary mucinous neoplasm (IPMN) specimens were analyzed by immunohistochemistry.
  
  
  RESULTS
  Loss of ACVR1B from pancreata of mice increased the proliferation of pancreatic epithelial cells, led to formation of acinar to ductal metaplasia, and induced focal inflammatory changes compared with control mice. Disruption of Acvr1b in LSL-KRAS(G12D);Pdx1-Cre mice accelerated the growth of pancreatic IPMNs compared with LSL-KRAS(G12D);Pdx1-Cre mice, but did not alter growth of pancreatic intraepithelial neoplasias. We associated perinuclear localization of the activated NOTCH4 intracellular domain to the apical cytoplasm of neoplastic cells with the expansion of IPMN lesions in Acvr1b(flox/flox);LSL-KRAS(G12D);Pdx1-Cre mice. Loss of the gene that encodes p16 (Cdkn2a) was required for progression of IPMNs to pancreatic ductal adenocarcinomas in Acvr1b(flox/flox);LSL-Kras(G12D);Pdx1-Cre mice. We also observed progressive loss of p16 in human IPMNs of increasing grades.
  
  
  CONCLUSIONS
  Loss of ACVR1B accelerates growth of mutant KRAS-induced pancreatic IPMNs in mice; this process appears to involve NOTCH4 and loss of p16. ACVR1B suppresses early stages of pancreatic tumorigenesis; the activin signaling pathway therefore might be a therapeutic target for pancreatic cancer.
authors.affiliation: The Department of Pathology, Columbia University Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors.forename: Wanglong
authors.initials: W
authors.lastname: Qiu
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors.forename: Sophia M
authors.initials: SM
authors.lastname: Tang
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors.forename: Sohyae
authors.initials: S
authors.lastname: Lee
authors.affiliation: The Department of Pathology, Columbia University Medical Center, New York, New York.
authors.forename: Andrew T
authors.initials: AT
authors.lastname: Turk
authors.affiliation: The Department of Pathology, Columbia University Medical Center, New York, New York.
authors.forename: Anthony N
authors.initials: AN
authors.lastname: Sireci
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors.forename: Anne
authors.initials: A
authors.lastname: Qiu
authors.affiliation: Plexus Medical Art, Denver, Colorado.
authors.forename: Christian
authors.initials: C
authors.lastname: Rose
authors.affiliation: Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York.
authors.forename: Chuangao
authors.initials: C
authors.lastname: Xie
authors.affiliation: Department of Obstetrics and Gynecology, Columbia University Medical Center, New York, New York.
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
authors.affiliation: Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida.
authors.forename: Hui-Ju
authors.initials: HJ
authors.lastname: Wen
authors.affiliation: Department of Cancer Biology, Mayo Clinic Cancer Center, Jacksonville, Florida.
authors.forename: Howard C
authors.initials: HC
authors.lastname: Crawford
authors.affiliation: Department of Systems Biology, Columbia University Medical Center, New York, New York.
authors.forename: Peter A
authors.initials: PA
authors.lastname: Sims
authors.affiliation: The Sol Goldman Pancreatic Cancer Research Center, Department of Pathology, The Johns Hopkins Medical Institutions, Baltimore, Maryland.
authors.forename: Ralph H
authors.initials: RH
authors.lastname: Hruban
authors.affiliation: The Department of Pathology, Columbia University Medical Center, New York, New York.
authors.forename: Helen E
authors.initials: HE
authors.lastname: Remotti
authors.affiliation: The Department of Pathology, Columbia University Medical Center, New York, New York; Herbert Irving Comprehensive Cancer Center, Columbia University Medical Center, New York, New York; Department of Otolaryngology and Head and Neck Surgery, Columbia University Medical Center, New York, New York. Electronic address: gs2157@columbia.edu.
authors.forename: Gloria H
authors.initials: GH
authors.lastname: Su
mesh_terms: D002288:Adenocarcinoma, Mucinous / Q000235:genetics / Q000401:mortality / Q000473:pathology; D000818:Animals; D063646:Carcinogenesis / Q000235:genetics; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D004195:Disease Models, Animal; D018450:Disease Progression; D017353:Gene Deletion; D016147:Genes, Tumor Suppressor; D020022:Genetic Predisposition to Disease; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008565:Membrane Proteins / Q000235:genetics*; D051379:Mice; D018345:Mice, Knockout; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D011897:Random Allocation; D060888:Real-Time Polymerase Chain Reaction; D015398:Signal Transduction; D015996:Survival Rate
chemical_list: C080034:Acrv1 protein, mouse; D008565:Membrane Proteins; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: PDA; Pancreas; TGF-β Superfamily; Tumor Suppressor