The unfolded protein response (UPR) is activated in pancreatic pathologies and suggested as a target for therapeutic intervention. In this study, we examined activating transcription factor 3 (ATF3), a mediator of the UPR that promotes acinar-to-ductal metaplasia (ADM) in response to pancreatic injury. Since ADM is an initial step in the progression to pancreatic ductal adenocarcinoma (PDAC), we hypothesized that ATF3 is required for initiation and progression of PDAC. We generated mice carrying a germline mutation of Atf3 (Atf3−/−) combined with acinar-specific induction of oncogenic KRAS (Ptf1acreERT/+KrasG12D/+). Atf3−/− mice with (termed APK) and without KRASG12D were exposed to cerulein-induced pancreatitis. In response to recurrent pancreatitis, Atf3−/− mice showed decreased ADM and enhanced regeneration based on morphological and biochemical analysis. Similarly, an absence of ATF3 reduced spontaneous pancreatic intraepithelial neoplasia (PanIN) formation and PDAC in Ptf1acreERT/+KrasG12D/+ mice. In response to injury, KRASG12D bypassed the requirement for ATF3 with a dramatic loss in acinar tissue and PanIN formation observed regardless of ATF3 status. Compared to Ptf1acreERT/+KrasG12D/+ mice, APK mice exhibited a significant decrease in pancreatic and total body weight, did not progress through to PDAC, and showed altered pancreatic fibrosis and immune cell infiltration. These findings suggest a complex, multifaceted role for ATF3 in pancreatic cancer pathology.
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The authors wish to acknowledge the ongoing support of several national research funding agencies for this work including the Canadian Institutes of Health Research (MOP#PJT166029), the Cancer Research Society of Canada, and the Rob Lutterman Foundation for Pancreatic Cancer Research. This work would not be possible without specific support from a London Regional Cancer Centre Catalyst Grant, co-supported by Keith Sammit and an internal bridge grant from the University of Western Ontario. NA and JT were funded by studentships from the Ontario Graduate Scholarships and Cancer Research and Technology Training (CaRTT) program. MFK was supported by an NSERC summer studentship. JS was supported by National Cancer Institute of the National Institutes of Health under award number K08CA234222.
Conflict of interest
The authors declare no competing interests.
All animal experiments were performed according to regulations established by the Animal Care and Use Committee at Western University (protocol #2017-001).
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Azizi, N., Toma, J., Martin, M. et al. Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer. Oncogene 40, 3118–3135 (2021). https://doi.org/10.1038/s41388-021-01771-z