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Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer
Oncogene
  • Nawab Azizi, Children's Health Research Institute, London, ON
  • Jelena Toma, Children's Health Research Institute, London, ON
  • Mickenzie Martin, Children's Health Research Institute, London, ON
  • Muhammad Faran Khalid, Children's Health Research Institute, London, ON
  • Fatemeh Mousavi, Children's Health Research Institute, London, ON
  • Phyo Wei Win, Children's Health Research Institute, London, ON
  • Maria Teresa Borrello, Centre de Recherche en Cancerologie de Marseille
  • Nina Steele, University of Michigan Medical School
  • Jiaqi Shi, University of Michigan Medical School
  • Marina Pasca di Magliano, University of Michigan Medical School
  • Christopher L. Pin, Children's Health Research Institute, London, ON
Document Type
Article
Publication Date
4-29-2021
URL with Digital Object Identifier
10.1038/s41388-021-01771-z
Abstract

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.

Citation Information
Nawab Azizi, Jelena Toma, Mickenzie Martin, Muhammad Faran Khalid, et al.. "Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer" Oncogene Vol. 40 Iss. 17 (2021) p. 3118 - 3135
Available at: http://works.bepress.com/christopher-pin/14/