Loss of NADPH-producing enzymes accelerates pancreatic precancerous lesions

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. Metabolism is extensively reprogrammed in cancer, but the metabolic alterations in precancerous lesions are understudied. Using RNA-sequencing and targeted metabolomics from isolated acinar cells we identified global changes in central carbon metabolism genes and metabolites during ADM formation. Overall design: Acinar cells were isolated from KrasLSL-G12D/+;Ptf1a-CreERTM/+ pancreas (n=3 individual pancreata; labeled as KC2, KC3, and KC5) or Ptf1a-CreERTM/+ control pancreas (n=1; labeled as CA2). 4-hydroxytamoxifen (2uM) was used to induce KrasG12D in cells over three days and compared with vehicle treatment after one day.