Abstract PR003: NADPH-producing enzymes restrict precancer progression in the pancreas

Abstract Rewired cell metabolism is a hallmark of cancer; however, metabolic changes in precancer development and progression are not well understood. Acinar-to-ductal metaplasia (ADM) is a reversible, injury-induced lesion in the pancreas that constitutes the first histological change en route to cancer. Persistent ADM can advance to precancerous lesions, like pancreatic intraepithelial neoplasia (PanIN), and further progress to pancreatic ductal adenocarcinoma (PDAC). We hypothesized that altered cell metabolism drives ADM formation and precancer progression. We used mouse models of pancreatic tumorigenesis, primary cell cultures, metabolomics, and RNA-sequencing to determine the role of NADPH-producing enzymes in pancreatic precancer progression. RNA-seq on ADM in ex vivo cultures showed an upregulation of redox and antioxidant pathways. NRF2-target genes, G6pdx (glucose-6-phosphate dehydrogenase) and Me1 (malic enzyme 1), were among the most differentially expressed and encode NADPH-producing enzymes. Previous work in the field shows that reactive oxygen species (ROS) control ADM; therefore, we hypothesized that decreased NADPH production, via Me1-loss or G6PD-deficiency, would increase ROS and promote ADM. To test this hypothesis, we obtained G6PD-deficient mice and generated Me1 flox/flox mice and bred them with the KC line (Kras LSL-G12D/+ ;Ptf1a Cre/+ ) to model pancreatic tumorigenesis. We found that KCG (KC;G6pdmutant) and KCM (KC;Me1flox/flox) mice develop ADM and PanIN faster and in higher numbers than KC counterparts. We also observed higher levels of ROS and lipid peroxidation in KCG pancreata. Furthermore, accelerated lesion progression was rescued by antioxidant treatment in vivo and in vitro. ADM cultures from healthy human acinar cells also upregulated G6PD and ME1. Additionally, ADM in human cells was accelerated by inhibiting glutathione biosynthesis, suggesting a shared mechanism for ADM and precancer progression in mice and humans. Together, these data support the hypothesis that NADPH-producing enzymes restrict precancer progression in a redox-dependent manner. Overall, this work describes key metabolic pathways that underlie pancreatic metaplasia and neoplasia, expanding our understanding of cancer initiation. Citation Format: Megan Radyk, Barbara Nelson, Christopher Halbrook, Mengrou Shan, Mariana Tannus Ruckert, Jonathan Alektiar, Brooke Lavoie, Hanna Hong, Alexander Wood, Lucie Salvatore, Peter Sajjakulnukit, Wei Yan, Matthew Perricone, Li Zhang, Gabriel Corfas, Filip Bednar, Justin Colacino, Timothy Frankel, Marina Pasca di Magliano, Yatrik Shah, Howard Crawford, Costas Lyssiotis. NADPH-producing enzymes restrict precancer progression in the pancreas [abstract]. In: Proceedings of the AACR Special Conference in Cancer Research: Cancer Evolution: The Dynamics of Progression and Persistence; 2025 Dec 4-6; Albuquerque, NM. Philadelphia (PA): AACR; Cancer Res 2025;85(23_Suppl):Abstract nr PR003.