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Smad4 is dispensable for normal pancreas development yet critical in progression and tumor biology of pancreas cancer

¹ Massachusetts General Hospital Cancer Center and Department of Medicine, Harvard Medical School, Boston, Massachusetts 02115, USA; ² Center for Applied Cancer Science, Belfer Foundation Institute for Innovative Cancer Science, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA; ³ Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts 02115, USA; ⁴ Department of Biochemistry and Biophysics, Comprehensive Cancer Center, and Diabetes Center, University of California at San Francisco, San Francisco, California 94143, USA; ⁵ Gastrointestinal Pathology Service, Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, Massachusetts 02115, USA; ⁶ Department of Medicine and Genetics, Harvard Medical School, Boston, Massachusetts 02115, USA

SMAD4 is inactivated in the majority of pancreatic ductal adenocarcinomas (PDAC) with concurrent mutational inactivation of the INK4A/ARF tumor suppressor locus and activation of the KRAS oncogene. Here, using genetically engineered mice, we determined the impact of SMAD4 deficiency on the development of the pancreas and on the initiation and/or progression of PDAC—alone or in combination with PDAC-relevant mutations. Selective SMAD4 deletion in the pancreatic epithelium had no discernable impact on pancreatic development or physiology. However, when combined with the activated KRAS^G12D allele, SMAD4 deficiency enabled rapid progression of KRAS^G12D-initiated neoplasms. While KRAS^G12D alone elicited premalignant pancreatic intraepithelial neoplasia (PanIN) that progressed slowly to carcinoma, the combination of KRAS^G12D and SMAD4 deficiency resulted in the rapid development of tumors resembling intraductal papillary mucinous neoplasia (IPMN), a precursor to PDAC in humans. SMAD4 deficiency also accelerated PDAC development of KRAS^G12D INK4A/ARF heterozygous mice and altered the tumor phenotype; while tumors with intact SMAD4 frequently exhibited epithelial-to-mesenchymal transition (EMT), PDAC null for SMAD4 retained a differentiated histopathology with increased expression of epithelial markers. SMAD4 status in PDAC cell lines was associated with differential responses to transforming growth factor- (TGF-) in vitro with a subset of SMAD4 wild-type lines showing prominent TGF--induced proliferation and migration. These results provide genetic confirmation that SMAD4 is a PDAC tumor suppressor, functioning to block the progression of KRAS^G12D-initiated neoplasms, whereas in a subset of advanced tumors, intact SMAD4 facilitates EMT and TGF--dependent growth.

[Keywords: Smad4; pancreatic cancer; epithelial-to-mesenchymal transition mouse models; TGF-]

Received August 4, 2006; revised version accepted September 14, 2006.

⁸ Corresponding authors.

E-MAIL nelbardeesy{at}partners.org; FAX (617) 643-3170.

⁹ E-MAIL Ron_depinho{at}dfci.harvard.edu; FAX (617) 632-6069.

Supplemental material is available at http://www.genesdev.org.

Article is online at http://www.genesdev.org/cgi/doi/10.1101/gad.1478706

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