The findings implicate epithelial tension and matricellular fibrosis in the aggressiveness of SMAD4 mutant pancreatic tumors and highlight STAT3 and mechanics as key drivers of this phenotype.
DPC4/SMAD4 mutations are associated with aggressive pancreatic cancer.In this issue of Cell, Whittle et al. demonstrate that Runx3 expression combined with Dpc4/Smad4 status can predict the metastatic propensity of pancreatic tumors, providing valuable guidance for personalized therapy for patients with pancreatic cancer.
SMAD4 is a gastrointestinal malignancy-specific tumor suppressor gene found mutated in one third of colorectal cancer specimens and half of pancreatic tumors.
We showed that the absence of Smad4 alone did not trigger pancreas tumor formation; however, it increased the expression of an inactivated form of Pten, suggesting a role of Pten in preventing Smad4-/- cells from undergoing malignancy.
Inhibition of STAT3 Tyr705 phosphorylation by Smad4 suppresses transforming growth factor beta-mediated invasion and metastasis in pancreatic cancer cells.
We show here that concomitant expression of Kras(G12D) and haploinsufficiency of the Smad4/Dpc4 tumor suppressor gene engenders a distinct class of pancreatic tumors, mucinous cystic neoplasms (MCNs), which culminate in invasive ductal adenocarcinomas.
Therefore, DPC4 inactivation by mutation or deletion appears to be very rare in PET, which confirms the current concept of unrelated mechanisms of tumorigenesis of endocrine versus exocrine pancreatic tumors.