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

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…

• EM
  Ellison Medical Foundation
• SW
  Samuel Waxman Cancer Research Foundation
• NI
  National Institutes of Health

  Awards: NIH K01, P01 CA117969
• HS
  Harvard Stem Cell Institute