Variability in energy metabolism enzymes in tumor cells.

Variability in gene expression is an important and largely unknown phenomenon responsible of tumor resistance to chemotherapy. Here, we show that energy metabolism proteins are highly variable, specially Glut1, G6PD, PKM2 and SDHA. In contrast, the variability of housekeeping proteins was low. We identified the PI3K/Akt/mTor pathway as the source of variability for PKM2.Variability was independent of the energy source used. However, cells grown on glucose down-regulate G6PDH and SDHA, promoting oxidative stress. Variability and chemotherapy plasticity were directly related, and the combination of drugs with opposite effect on the expression of plastic proteins resulted in positive synergy. Human solid tumor cells displayed higher variability in metabolic enzymes than cultured cells. The most aggressive tumors showed higher variability than less aggressive ones. This suggests that variability in energy metabolism enzymes could be a biomarker for tumor stratification and therapy election. In order to reveal the origin of the variability of metabolic enzymes, we performed single-cell transcriptomic analysis of HeLa cells. 96 cells were sorted and sequenced for this study.