The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis

Viviane Palhares Muniz; J Matthew Barnes; Seema Paliwal; Xuefeng Zhang; Xiaoyun Tang; Songhai Chen; Kokou D Zamba; Joseph J Cullen; David K Meyerholz; Shari Meyers; Steven R Grossman; Michael D Henry; J Nathan Davis; Dawn E Quelle

doi:10.1158/1541-7786.MCR-10-0475

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The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis

Journal article

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The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis

Viviane Palhares Muniz, J Matthew Barnes, Seema Paliwal, Xuefeng Zhang, Xiaoyun Tang, Songhai Chen, Kokou D Zamba, Joseph J Cullen, David K Meyerholz, Shari Meyers, …

Molecular cancer research, Vol.9(7), pp.867-877

07/2011

DOI: 10.1158/1541-7786.MCR-10-0475

PMCID: PMC3140613

PMID: 21636682

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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.

Cell Proliferation

Luciferases - analysis

Neoplasm Invasiveness

Humans

Pancreatic Neoplasms - pathology

Tumor Suppressor Protein p53 - metabolism

Pancreatic Neoplasms - genetics

Mice, SCID

Carcinoma, Pancreatic Ductal - pathology

Tumor Suppressor Protein p53 - genetics

Carcinoma, Pancreatic Ductal - genetics

Neoplasms, Experimental - pathology

Neoplasm Metastasis

Animals

Neoplasms, Experimental - genetics

Cell Line, Tumor

Mice

Tumor Suppressor Protein p14ARF - genetics

Tumor Suppressor Protein p14ARF - metabolism

Genes, Tumor Suppressor

Details

Title: Subtitle: The ARF tumor suppressor inhibits tumor cell colonization independent of p53 in a novel mouse model of pancreatic ductal adenocarcinoma metastasis
Creators: Viviane Palhares Muniz - Molecular and Cellular Biology Graduate Program, The University of Iowa, Iowa City, Iowa 52242, USA
J Matthew Barnes
Seema Paliwal
Xuefeng Zhang
Xiaoyun Tang
Songhai Chen
Kokou D Zamba
Joseph J Cullen
David K Meyerholz
Shari Meyers
Steven R Grossman
Michael D Henry
J Nathan Davis
Dawn E Quelle
Resource Type: Journal article
Publication Details: Molecular cancer research, Vol.9(7), pp.867-877
DOI: 10.1158/1541-7786.MCR-10-0475
PMID: 21636682
PMCID: PMC3140613
NLM abbreviation: Mol Cancer Res
ISSN: 1541-7786
eISSN: 1557-3125
Publisher: United States
Grant note: I01 BX001318 / BLRD VA R01 CA090367-08 / NCI NIH HHS R01 CA090367-09 / NCI NIH HHS R21 CA127031 / NCI NIH HHS R03 CA143763 / NCI NIH HHS R21-CA127031 / NCI NIH HHS R21 CA127031-01A2 / NCI NIH HHS R01-CA090367 / NCI NIH HHS R01 CA090367-10 / NCI NIH HHS R01 CA090367 / NCI NIH HHS R21 CA127031-02 / NCI NIH HHS R03-CA143763 / NCI NIH HHS R03 CA143763-01 / NCI NIH HHS
Language: English
Date published: 07/2011
Academic Unit: Radiology; Molecular Physiology and Biophysics; Pathology; Iowa Neuroscience Institute; Biostatistics; Surgery; Radiation Oncology; Neuroscience and Pharmacology; Urology; Internal Medicine
Record Identifier: 9983997319202771

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