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

## TL;DR

This study shows that removing ATF3 in acinar cells limits the progression of pancreatic cancer caused by KRASG12D mutations.

## Contribution

The study reveals that ATF3 acts in a cell-specific manner to promote KRASG12D-driven pancreatic cancer.

## Key findings

- APK acinar cells showed reduced oncogenic pathways and acinar-to-ductal metaplasia (ADM) formation.
- APK organoids had altered gene expression, morphology, and reduced viability compared to controls.
- In vivo, ATF3 deletion restricted neoplastic progression and KRAS signaling in pancreatic tissue.

## 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.