Glucose-6-phosphate dehydrogenase deficiency accelerates pancreatic acinar-to-ductal metaplasia.

Autor:	Radyk MD; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA., Nelson BS; Doctoral Program in Cancer Biology, University of Michigan, Ann Arbor, USA., Halbrook CJ; Department of Molecular Biology and Biochemistry, University of California Irvine, Irvine, CA, USA.; University of California Irvine Chao Family Comprehensive Cancer Center, Orange, CA, USA., Wood A; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA., Lavoie B; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA., Salvatore L; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA., Corfas G; Kresge Hearing Research Institute and Dept. of Otolaryngology, Head and Neck Surgery, University of Michigan, Ann Arbor, MI, USA., Colacino JA; Department of Environmental Health Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.; Department of Nutritional Sciences, School of Public Health, University of Michigan, Ann Arbor, MI, USA.; Program in the Environment, College of Literature, Sciences, and the Arts, University of Michigan, Ann Arbor, MI, USA.; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA., Shah YM; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA., Crawford HC; Department of Surgery, Henry Ford Pancreatic Cancer Center, Henry Ford Health System, Detroit, MI, USA., Lyssiotis CA; Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, MI, USA.; University of Michigan Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.; Department of Internal Medicine, Division of Gastroenterology and Hepatology, University of Michigan, Ann Arbor, MI, USA.
Jazyk:	angličtina
Zdroj:	BioRxiv : the preprint server for biology [bioRxiv] 2023 Nov 08. Date of Electronic Publication: 2023 Nov 08.
DOI:	10.1101/2023.11.06.565895
Abstrakt:	Activating mutations in KRAS extensively reprogram cellular metabolism to support the continuous growth, proliferation, and survival of pancreatic tumors. Targeting these metabolic dependencies are promising approaches for the treatment of established tumors. However, metabolic reprogramming is required early during tumorigenesis to provide transformed cells selective advantage towards malignancy. Acinar cells can give rise to pancreatic tumors through acinar-to-ductal metaplasia (ADM). Dysregulation of pathways that maintain acinar homeostasis accelerate tumorigenesis. During ADM, acinar cells transdifferentiate to duct-like cells, a process driven by oncogenic KRAS . The metabolic reprogramming that is required for the transdifferentiation in ADM is unclear. We performed transcriptomic analysis on mouse acinar cells undergoing ADM and found metabolic programs are globally enhanced, consistent with the transition of a specialized cell to a less differentiated phenotype with proliferative potential. Indeed, we and others have demonstrated how inhibiting metabolic pathways necessary for ADM can prevent transdifferentiation and tumorigenesis. Here, we also find NRF2-target genes are differentially expressed during ADM. Among these, we focused on the increase in the gene coding for NADPH-producing enzyme, Glucose-6-phosphate dehydrogenase (G6PD). Using established mouse models of Kras G12D -driven pancreatic tumorigenesis and G6PD-deficiency, we find that mutant G6pd accelerates ADM and pancreatic intraepithelial neoplasia. Acceleration of cancer initiation with G6PD-deficiency is dependent on its NADPH-generating function in reactive oxygen species (ROS) management, as opposed to other outputs of the pentose phosphate pathway. Together, this work provides new insights into the function of metabolic pathways during early tumorigenesis.
Databáze:	MEDLINE
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