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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-β (TGF-β) in vitro with a subset of SMAD4 wild-type lines showing prominent TGF-β-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-β-dependent growth.

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