Loss of Activating transcription factor 3 restricts KRASG12D’s ability to promote PanIN progression through epithelial specific transcriptional regulation

Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer-related deaths in North America with ~12% survival 5 years after diagnosis. Risk factors for PDAC, including smoking and chronic pancreatitis, trigger the unfolded protein response (UPR) and global loss of Activating Transcription Factor 3 (ATF3), a mediator of the UPR, restricts preneoplastic progression in mice expressing oncogenic KRAS (KRASG12D). Since ATF3 is expressed in multiple cell compartments during PDAC progression, the goal of this study was to determine epithelial-specific roles for ATF3 during pre-neoplastic stages of PDAC. APK and AacinarPK tissue showed restricted neoplasia progression compared to Ptf1acreERT/+KRASG12D/+ mice. Ptf1acreERT/+KRASG12D/+ and APK organoids showed differential gene expression, and morphology, with APK organoids having reduced viability over time. This study reveals an epithelial-specific role for ATF3 in restricting KRASG12D -mediated PDAC and indicates ATF3 has functions in multiple cell compartments during PDAC progression.