title: The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis.
abstract: Pancreatic ductal adenocarcinoma (PDAC) is an incurable, highly metastatic disease that is largely resistant to existing treatments. A better understanding of the genetic basis of PDAC metastasis should facilitate development of improved therapies. To that end, we developed a novel mouse xenograft model of PDAC metastasis to expedite testing of candidate genes associated with the disease. Human PDAC cell lines BxPC-3, MiaPaCa-2, and Panc-1 stably expressing luciferase were generated and introduced by intracardiac injections into immunodeficient mice to model hematogenous dissemination of cancer cells. Tumor development was monitored by bioluminescence imaging. Bioluminescent MiaPaCa-2 cells most effectively recapitulated PDAC tumor development and metastatic distribution in vivo. Tumors formed in nearly 90% of mice and in multiple tissues, including normal sites of PDAC metastasis. Effects of p14ARF, a known suppressor of PDAC, were tested to validate the model. In vitro, p14ARF acted through a CtBP2-dependent, p53-independent pathway to inhibit MiaPaCa-2-invasive phenotypes, which correlated with reduced tumor cell colonization in vivo. These findings establish a new bioluminescent mouse tumor model for rapidly assessing the biological significance of suspected PDAC metastasis genes. This system may also provide a valuable platform for testing innovative therapies.
authors.affiliation: Molecular and Cellular Biology Graduate Program, The University of Iowa, Iowa City, Iowa 52242, USA.
authors.forename: Viviane Palhares
authors.initials: VP
authors.lastname: Muniz
authors.forename: J Matthew
authors.initials: JM
authors.lastname: Barnes
authors.forename: Seema
authors.initials: S
authors.lastname: Paliwal
authors.forename: Xuefeng
authors.initials: X
authors.lastname: Zhang
authors.forename: Xiaoyun
authors.initials: X
authors.lastname: Tang
authors.forename: Songhai
authors.initials: S
authors.lastname: Chen
authors.forename: Kokou D
authors.initials: KD
authors.lastname: Zamba
authors.forename: Joseph J
authors.initials: JJ
authors.lastname: Cullen
authors.forename: David K
authors.initials: DK
authors.lastname: Meyerholz
authors.forename: Shari
authors.initials: S
authors.lastname: Meyers
authors.forename: J Nathan
authors.initials: JN
authors.lastname: Davis
authors.forename: Steven R
authors.initials: SR
authors.lastname: Grossman
authors.forename: Michael D
authors.initials: MD
authors.lastname: Henry
authors.forename: Dawn E
authors.initials: DE
authors.lastname: Quelle
mesh_terms: D000818:Animals; D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D016147:Genes, Tumor Suppressor; D006801:Humans; D008156:Luciferases / Q000032:analysis; D051379:Mice; D016513:Mice, SCID; D009361:Neoplasm Invasiveness; D009362:Neoplasm Metastasis; D009374:Neoplasms, Experimental / Q000235:genetics / Q000473:pathology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000473:pathology*; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics / Q000378:metabolism*; D016159:Tumor Suppressor Protein p53 / Q000235:genetics / Q000378:metabolism
chemical_list: D025803:Tumor Suppressor Protein p14ARF; D016159:Tumor Suppressor Protein p53; D008156:Luciferases