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

Abstract

An altered energy metabolism is 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. Since it is not clear whether all these targets are required and how the overall metabolic response is shaped, we here dissect the effect of MYCN targets on the pathway individually and in combination using a computational modeling approach. We develop a first mathematical model of the energy metabolism in neuroblastoma cells based on our published experimental data. The analysis shows that MYCN overexpression overall leads to Warburg-like flux alterations with characteristic changes for the individual MYCN targets highlighting that MYCN targets can have opposing and sometimes unexpected effects. Interestingly, not all described MYCN targets contribute to notable flux alterations, at least in glycolysis. Our model moreover predicts a potential bistability of the cellular metabolism with an occurrence of a low-flux state likely representing quiescence. Overall, our study highlights the importance of analysing perturbations such as expression changes in the context of realistic pathways capturing their specific interactions and complex regulations.