Analysis of the tumor-initiating and metastatic capacity of PDX1-positive cells from the adult pancreas

• Published in: Proceedings of the National Academy of Sciences - PNAS Vol. 111; no. 9; pp. 3466 - 3471
• Main Authors: Ischenko, Irene, Petrenko, Oleksi, Hayman, Michael J.
• Format: Journal Article
• Language: English
• Published: United States National Academy of Sciences 04-03-2014; National Acad Sciences
• Subjects: Animals; Biological Sciences; Blotting, Western; Cancer; Cell growth; Cell lines; Cellular differentiation; Flow Cytometry; Genotype & phenotype; Homeodomain Proteins - metabolism; Kinases; Lung Neoplasms - pathology; Lung Neoplasms - secondary; MAP Kinase Signaling System - physiology; Metastasis; Mice; Mice, Knockout; Mice, Nude; Mutation; Mutation, Missense - genetics; Neoplasm Metastasis - physiopathology; Pancreas; Pancreatic cancer; Pancreatic cells; Pancreatic neoplasms; Pancreatic Neoplasms - metabolism; Pancreatic Neoplasms - physiopathology; Polymerase Chain Reaction; Proto-Oncogene Proteins c-myc - metabolism; Proto-Oncogene Proteins p21(ras) - genetics; Stem cells; Trans-Activators - metabolism; Tumor cell line; Tumor Suppressor Protein p53 - genetics; Tumors; cell of origin; pancreatic ductal adenocarcinoma
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.1319911111

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.