Mayers, Torrence et al. investigated whether the tissue of origin affects branched-chain amino acid (BCAA) metabolism, as elevated plasma levels of BCAAs are present in mice with pancreatic ductal adenocarcinoma (PDAC) but not in non-small-cell lung cancer (NSCLC) induced by oncogenic KRAS and loss of p53. KrasG12D/+;Trp53flox/flox (KP) mice were either crossed with a pancreatic and duodenal homeobox 1 (Pdx1) promoter-driven Cre strain to induce Trp53 knockout in the pancreas or given viral Cre in the lungs to generate PDAC and NSCLC tumours, respectively. The authors fed the mice with 13C-labelled BCAAs (leucine and valine), and levels of BCAA metabolites were measured. NSCLC tumours had higher levels of labelled BCAAs relative to normal lung tissue, whereas PDAC tumours did not (compared with normal pancreas), suggesting that lung tumours have higher uptake of BCAAs.
BCAAs can be incorporated into proteins or catabolized into branched chain α-ketoacids (BCKAs) that are either secreted, fed into the tricarboxylic acid (TCA) cycle or used to regenerate BCAAs. 13C labelling revealed that NSCLC tumours, but not PDAC tumours, had high levels of BCAA-derived proteins. NSCLC tumours also had high levels of the leucine-derived BCKA α-ketoisocaproate (KIC), but no other changes in BCAA metabolites were observed in these tumours. Furthermore, labelling of metabolites downstream of KIC was high in the livers of mice with NSCLC tumours, indicating that these tumours secrete excess KIC.
This is a preview of subscription content, access via your institution