Acinar-specific loss of activating transcription factor 3 restricts KRASG12D mediated transcriptional changes and PanIN progression

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 (KRAS^G12D). 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 KRAS^G12D with (Ptf1a^creERT/+KRAS^G12D/+) or without ATF3 (Atf3^-/-Ptf1a^creERT/+KRAS^G12D/+; APK) were characterized before and after pancreatic injury. Additionally, mice allowing acinar-specific Atf3 deletion and KRAS^G12D expression (A^acinarPK) were compared to Ptf1a^creERT/+KRAS^G12D/+ and APK mice following injury. RNA-seq revealed reduced oncogenic pathways in APK acinar cells consistent with reduced ADM formation in APK cultures. Ptf1a^creERT/+KRAS^G12D/+ and APK organoids showed differential gene expression and morphology, with APK organoids exhibiting reduced viability. In vivo, APK and A^acinarPK tissue showed restricted neoplastic progression and KRAS signaling compared to Ptf1a^creERT/+KRAS^G12D/+ mice. This study indicates ATF3 works in a cell autonomous fashion, and its absence restricts KRAS^G12D-mediated PDAC.