Acinar-to-ductal metaplasia in the pancreas requires a glycolytic switch and functional mitochondria

Abstract

AbstractReprogramming of the cellular metabolism is a hallmark of pancreatic cancer, yet it remains unclear at what stage during carcinogenesis it occurs. Here, we investigated the metabolic requirements for acinar-to-ductal metaplasia (ADM), the first step in pancreatic carcinogenesis. We detected increased glycolytic marker expression in human ADM suggesting that a metabolic switch occurs during ADM formation. We report that this switch was similarly required for ADM formation in different oncogenic mouse models (KRAS, PI3K, and MEK1) and in ligand-induced ADM in mouse wild-type acini.In addition, we show that a functional electron transport chain (ETC), but not mitochondrial ATP production, was essential to ADM formation. We conclude that the ETC provides NAD+for thede novosynthesis of serine from glycolysis intermediates. Our findings demonstrate that metabolic programming is essential for the initiation of pancreatic carcinogenesis and thus identifies potential targets for metabolic intervention.