NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions
Date: | April 8, 2026 |
PMID: | |
Category: | N/A |
Authors: | Megan D Radyk, Barbara S Nelson, Mariana Tannus Ruckert, Christopher J Halbrook, Mengrou Shan, Jonathan M Alektiar, Brooke L Lavoie, Lucie Salvatore, Wei Yan, Matthew D Perricone, Kathryn Buscher, Alexander Wood, Hanna S Hong, Peter Sajjakulnukit, Li Zhang, Gabriel Corfas, Filip Bednar, Timothy L Frankel, Marina Pasca di Magliano, Justin A Colacino, Yatrik M Shah, Howard C Crawford, Costas A Lyssiotis |
Abstract: |
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Acinar-to-ductal metaplasia (ADM) is a reversible cell state that facilitates pancreas repair following injury. Oncogenic KRAS mutations can progress ADM to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC). However, the metabolic alterations in these precancerous lesions are understudied. Here, we identify global changes in central carbon metabolism genes and metabolites during ADM formation. In particular, NRF2-target genes are significantly induced in ADM. Among these, we focus on genes encoding NADPH-producing enzymes glucose-6-phosphate dehydrogenase (G6PD) and malic enzyme 1 (ME1), which participate in the regulation of oxidative stress. In mouse models of pancreatic tumourigenesis, G6PD deficiency or Me1 loss increases reactive oxygen species and lipid peroxidation, which is accompanied by accelerated formation of ADM and PanIN lesions. Notably, Me1 loss, but not G6PD deficiency, promotes faster PDAC progression. We demonstrate that oxidative stress is required for ADM, as pharmacological antioxidant treatment attenuates ADM progression in vivo and ex vivo. Conversely, depleting the antioxidant glutathione promotes precancerous lesions in primary human acinar cells and in mice. Together, our findings shed light on metabolic reprogramming in the precancerous pancreas.
Acknowledgements:
The content of this article is solely the responsibility of the authors and does not necessarily represent the official views of the National Cancer Institute, or the National Institute of Health.
The Translational and Basic Science Research in Early Lesions (TBEL) Research Consortia is supported and funded by grants from the National Cancer Institute and the National Institutes of Health under the following award numbers:
Project Number: | Awardee Organization |
U54CA274374 | Fred Hutchinson Cancer Center |
U54CA274375 | Houston Methodist Research Institute |
U54CA274370 | Johns Hopkins University |
U54CA274371 | UT MD Anderson Cancer Center |
U54CA274367 | Vanderbilt University Medical Center |
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