ITGAV and SMAD4 influence the progression and clinical outcome of pancreatic ductal adenocarcinoma.

Abstract

Pancreatic ductal adenocarcinoma (PDAC) is a very aggressive and lethal malignancy with limited treatment options, a fact that underscores the urgent need for more effective therapies to improve patient outcomes. Preclinical studies have shown promise for αV integrin-targeted therapies; however, clinical trials have been disappointing, highlighting the need for further research. In this study, we demonstrate that integrin subunit alpha V (ITGAV) signals through both mothers against decapentaplegic homolog 4 (SMAD4)-dependent or SMAD4-independent pathways, depending on the genetic context. In SMAD4-positive PDAC cells, ITGAV contributes to the transforming growth factor-beta (TGF-β) signaling pathway to regulate proliferation, migration, and invasion. Conversely, in SMAD4-negative PDAC cells, ITGAV influences only proliferation and migration via activation of the mitogen-activated protein kinase (MAPK)/extracellular signal-related kinase (ERK) pathway. High levels of ITGAV are also associated with poor prognostic outcomes in SMAD4 wild-type patients but are not prognostic in SMAD4 mutant patients. Thus, ITGAV contributes to different patterns of PDAC progression. These findings suggest that stratifying PDAC patients based on both SMAD4 status and ITGAV expression could inform more effective integrin-targeted treatment strategies.