Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the 3rd leading cause of cancer 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). Global deletion of Activating Transcription Factor 3 (ATF3), a UPR mediator, restricts preneoplastic progression in mice expressing oncogenic KRAS (KRASG12D). However, ATF3 is expressed in malignant and non-malignant cells suggesting it may affect multiple cell compartments in PDAC. Therefore, the goal of this study was to determine if ATF3 has epithelial-specific roles during PDAC initiation. Epithelial cells from mice expressing KRASG12D with (Ptf1acreERT/+KRASG12D/+) or without ATF3 (Atf3-/-Ptf1acreERT/+KRASG12D/+; APK) were characterized before and after pancreatic injury. Additionally, mice allowing acinar-specific Atf3 deletion and KRASG12D expression (AacinarPK) were compared to Ptf1acreERT/+KRASG12D/+ and APK mice following injury. RNA-seq revealed reduced oncogenic pathways in APK acinar cells consistent with reduced ADM formation in APK cultures. Ptf1acreERT/+KRASG12D/+ and APK organoids showed differential gene expression and morphology, with APK organoids exhibiting reduced viability. In vivo, APK and AacinarPK tissue showed restricted neoplastic progression and KRAS signaling compared to Ptf1acreERT/+KRASG12D/+ mice. This study indicates ATF3 works in a cell autonomous fashion, and its absence restricts KRASG12D-mediated PDAC.