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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

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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More Information

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/

Users with ORCIDS

ORCID for Maria Teresa Borrello: ORCID iD orcid.org/0000-0003-1365-1358

Catalogue record

Date Deposited: 23 Sep 2024 08:55
Last Modified: 23 Sep 2024 09:00

Contributors

Author: Maria Teresa Borrello ORCID iD
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 Sciences

Subjects

Sciences > Biomedical Sciences
Sciences > Pharmacy and Pharmacology
Sciences

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