KRAS-induced activation of YAP and AP-1 leads to rapid pancreatic cancer development.

Abstract

The development of Pancreatic Ductal Adenocarcinoma (PDAC) strongly depends on mutations in KRAS signaling and activation of its downstream effectors. YAP/TAZ, effectors of the Hippo signaling pathway, have recently been linked to aberrant KRAS signaling in the pancreas. However, the exact role of YAP in pancreatic cancer development remains a controversy. To study the effect of YAP activation in the adult pancreas, I established two different pancreas-specific Lats1/2 knockout mouse models and confirmed my findings in a KRAS-dependent mouse model. Activation of YAP in the whole pancreas lead to the rapid development of ADM and PDAC lesions, whereas activation of YAP specifically in acinar cells resulted in the development of ADM only. YAP-driven pancreatic cancer development was accompanied by a significant increase of AP-1 activity. Mechanistically, I show that YAP and AP-1 interact both directly and indirectly via the TEAD transcription factors. Furthermore, YAP and AP-1 were also synergistically activated in a KRAS-driven mouse model and in human PDAC specimens, emphasizing the clinical importance of my findings.