A computational model elucidates the effects of oncogene-induced expression alterations on the energy metabolism of neuroblastoma

Abstract

Alterations in energy metabolism are recognized as a hallmark of cancer. Experimental evidence shows that oncogenes play a key role in the reprogramming of metabolism. In neuroblastoma, the oncogene MYCN, a main risk factor of poor prognosis, has been demonstrated to lead to expression changes in numerous glycolytic enzymes. It is not clear whether all these targets are required and how they jointly shape metabolic responses. Here we use a computational modeling approach to dissect the effects of MYCN targets on the pathway individually and in combination. We develop the first mathematical model of the energy metabolism in neuroblastoma cells based on our published experimental data. The analysis shows that overall, MYCN overexpression leads to Warburg-like flux alterations. However, individual MYCN targets can have opposing and sometimes unexpected effects. Interestingly, not all of them contribute to notable flux alterations, at least with regard to glycolysis. Moreover, our model predicts a potential bistability of cellular metabolism with a low-flux state likely representing a non-proliferative state. Overall, our study emphasizes that perturbations such as expression changes should be analysed in the context of realistic pathway models, in which specific interactions and complex regulations are captured.