Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most aggressive tumors with poor prognosis and inadequate response to treatment, such as gemcitabine (Gem), the first-line chemotherapeutic drug. Understanding the molecular determinants that control drug resistance to Gem is critical to predict potentially responsive patients and improve the benefits of Gem therapy. Emerging evidence suggests that certain developmental pathways, such as Hippo signaling, are aberrated and play important roles in Gem resistance in cancers. Although Hippo signaling has been reported to play a role in chemoresistance in cancers, it has not been clarified which specific target gene(s) functionally mediates the effect. In the present study, we found that YAP serves as a potent barrier for the cellular sensitivity of PDAC cells to Gem. We then identified and characterized laminin subunit beta 3 (LAMB3) as a bona fide target of YAP-TEAD4 to amplify YAP signaling via a feedback loop. Such a YAP-LAMB3 axis is critical to induce epithelial-mesenchymal transition and mediate Gem resistance. Taken together, we uncovered that YAP-LAMB3 axis is an important regulator of Gem, thus providing potential therapeutic targets for overcoming Gem resistance in PDAC.