ALDH1L2 regulates reactive oxygen species and acinar-to-ductal metaplasia in the pancreas

Abstract Acinar-to-ductal metaplasia (ADM) contributes to pancreatic repair after injury 1 . However, persistent ADM, combined with KRAS mutation, leads to the development of precancerous pancreatic intraepithelial neoplasia (PanIN) that can progress into pancreatic ductal adenocarcinoma (PDAC) 2 . While PDAC development is well documented, the metabolic rewiring that occurs during early events such as ADM is poorly understood. Here we show that aldehyde dehydrogenase 1 family member L2 (ALDH1L2), an NADPH-producing mitochondrial enzyme of the one-carbon pathway, limits reactive oxygen species (ROS) and formate production in pancreatic acinar cells. However, ALDH1L2 expression decreases progressively during ADM and is completely absent in pancreatic ductal cells. ALDH1L2 loss elevates ROS and promotes ADM in a model of pancreatitis and accelerates tumour progression in models of pancreatic cancer. We also show that formate increases during PDAC progression in mice and humans. Overall, our findings identify ROS as a driver of ADM and suggest that circulating formate may serve as a biomarker for PDAC progression.