title: Analysis of the tumor-initiating and metastatic capacity of PDX1-positive cells from the adult pancreas.
abstract: Pancreatic cancer is one of the deadliest human malignancies. A striking feature of pancreatic cancer is that activating Kras mutations are found in ∼90% of cases. However, apart from a restricted population of cells expressing pancreatic and duodenal homeobox 1 (PDX1), most pancreatic cells are refractory to Kras-driven transformation. In the present study, we sought to determine which subsets of PDX1+ cells may be responsible for tumor growth. Using the Lox-Stop-Lox-KrasG12D genetic mouse model of pancreatic carcinogenesis, we isolated a population of KrasG12D-expressing PDX1+ cells with an inherent capacity to metastasize. This population of cells bears the surface phenotype of EpCAM+CD24+CD44+CD133-SCA1- and is closer in its properties to stem-like cells than to more mature cell types. We further demonstrate that the tumorigenic capacity of PDX1+ cells is limited, becoming progressively lost as the cells acquire a mature phenotype. These data are consistent with the hypothesis that the adult pancreas harbors a dormant progenitor cell population that is capable of initiating tumor growth under conditions of oncogenic stimulation. We present evidence that constitutive activation of the mitogen-activated protein kinase (MAPK/ERK) signaling and stabilization of the MYC protein are the two main driving forces behind the development of pancreatic cancer cells with stem-cell-like properties and high metastatic potential. Our results suggest that pancreatic cells bearing Kras mutation can be induced to differentiate into quasi-normal cells with suppressed tumorigenicity by selective inhibition of the MAPK/ERK/MYC signaling cascade.
authors.affiliation: Departments of Molecular Genetics and Microbiology and Pathology, Stony Brook University, Stony Brook, NY 11794.
authors.forename: Irene
authors.initials: I
authors.lastname: Ischenko
authors.forename: Oleksi
authors.initials: O
authors.lastname: Petrenko
authors.forename: Michael J
authors.initials: MJ
authors.lastname: Hayman
mesh_terms: D000818:Animals; D015153:Blotting, Western; D005434:Flow Cytometry; D018398:Homeodomain Proteins / Q000378:metabolism*; D008175:Lung Neoplasms / Q000473:pathology / Q000556:secondary*; D020935:MAP Kinase Signaling System / Q000502:physiology*; D051379:Mice; D018345:Mice, Knockout; D008819:Mice, Nude; D020125:Mutation, Missense / Q000235:genetics; D009362:Neoplasm Metastasis / Q000503:physiopathology*; D010190:Pancreatic Neoplasms / Q000378:metabolism / Q000503:physiopathology*; D016133:Polymerase Chain Reaction; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics*; D015534:Trans-Activators / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
chemical_list: D018398:Homeodomain Proteins; C489428:Myc protein, mouse; D016271:Proto-Oncogene Proteins c-myc; D015534:Trans-Activators; D016159:Tumor Suppressor Protein p53; C084010:pancreatic and duodenal homeobox 1 protein; C495971:Hras protein, mouse; D016283:Proto-Oncogene Proteins p21(ras)
keywords: cell of origin; pancreatic ductal adenocarcinoma