Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer
Azizi, Nawab, Toma, Jelena, Martin, Mickenzie, Khalid, Muhammad Faran, Mousavi, Fatemeh, Win, Phyo Wei, Borrello, Maria Teresa, Steele, Nina, Shi, Jiaqi, di Magliano, Marina Pasca and Pin, Christopher L. (2021) Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer. Loss of activating transcription factor 3 prevents KRAS-mediated pancreatic cancer, 40. pp. 3118-3135. ISSN 0950-9232
Item Type: | Article |
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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
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Depositing User: Teresa Borrello |
Identifiers
Item ID: 18149 |
Identification Number: https://doi.org/10.1038/s41388-021-01771-z |
ISSN: 0950-9232 |
URI: http://sure.sunderland.ac.uk/id/eprint/18149 | Official URL: https://pubmed.ncbi.nlm.nih.gov/33864001/ |
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Catalogue record
Date Deposited: 23 Sep 2024 08:55 |
Last Modified: 23 Sep 2024 09:00 |
Author: | Maria Teresa Borrello |
Author: | Nawab Azizi |
Author: | Jelena Toma |
Author: | Mickenzie Martin |
Author: | Muhammad Faran Khalid |
Author: | Fatemeh Mousavi |
Author: | Phyo Wei Win |
Author: | Nina Steele |
Author: | Jiaqi Shi |
Author: | Marina Pasca di Magliano |
Author: | Christopher L. Pin |
University Divisions
Faculty of Health Sciences and Wellbeing > School of Pharmacy and Pharmaceutical SciencesSubjects
Sciences > Biomedical SciencesSciences > Pharmacy and Pharmacology
Sciences
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