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NADPH-producing enzymes restrict the formation of pancreatic precancerous lesions
Megan D Radyk1,2, Barbara S Nelson1,3, Mariana Tannus Ruckert1
1Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.
Abstract:
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.
Insights
Pancreatic metaplasia involves metabolic changes, particularly NRF2-target genes like G6PD and ME1, which regulate oxidative stress. Oxidative stress drives precancerous lesion formation, impacting pancreatic ductal adenocarcinoma progression.
Area of Science:
- Metabolic reprogramming in cancer biology
- Pancreatic cancer research
- Cellular stress response mechanisms
Background:
- Acinar-to-ductal metaplasia (ADM) is a reversible cell state crucial for pancreas repair.
- Oncogenic KRAS mutations can drive ADM progression to pancreatic intraepithelial neoplasia (PanIN) and pancreatic ductal adenocarcinoma (PDAC).
- Metabolic alterations in precancerous pancreatic lesions remain understudied.
Purpose of the Study:
- To investigate global changes in central carbon metabolism during ADM formation.
- To elucidate the role of NADPH-producing enzymes (G6PD, ME1) and oxidative stress in pancreatic precancerous lesions.
- To understand the impact of metabolic reprogramming on PDAC progression.
Main Methods:
- Analysis of central carbon metabolism genes and metabolites in ADM.
- Utilizing mouse models of pancreatic tumorigenesis with G6PD or ME1 deficiency.
- Pharmacological manipulation of oxidative stress and glutathione levels in vitro and in vivo.
- Assessment of ADM, PanIN formation, and PDAC progression.
Main Results:
- ADM formation is associated with significant changes in central carbon metabolism and induction of NRF2-target genes.
- G6PD and ME1, key NADPH-producing enzymes, are involved in regulating oxidative stress.
- G6PD deficiency or ME1 loss increases reactive oxygen species and lipid peroxidation, accelerating ADM and PanIN formation.
- ME1 loss, unlike G6PD deficiency, accelerates PDAC progression.
- Pharmacological antioxidant treatment attenuates ADM progression, while glutathione depletion promotes precancerous lesions.
Conclusions:
- Oxidative stress is a required driver for ADM.
- Metabolic reprogramming, particularly involving NADPH-producing enzymes and oxidative stress regulation, plays a critical role in pancreatic precancerous lesion development.
- Targeting metabolic pathways offers potential therapeutic strategies for PDAC prevention and treatment.
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