Why the tumor cell metabolism is not that abnormal

Abstract

The cell energy metabolism is a multifactorial and evolving process that we address with a theoretical approach in order to decipher the functioning of the core system of the glycolysis-OXPHOS relationship. The model is based on some key experimental observations and well established facts. It emphasizes the role of lactate as a substrate, as well as the central role of pyruvate in the regulation of the metabolism. The simulations show how imposed environmental constraints and imposed energy requirements push the cell to adapt its metabolism to sustain its needs. The results highlight the cooperativeness of the two metabolic modes and allows to revisit the notions of metabolic switch and metabolic reprogramming. Our results thus tend to show that the Warburg effect is not an inherent characteristic of the tumor cell, but a spontaneous and transitory adaptation mechanism to a disturbed environment. This means that the tumor cell metabolism is not fundamentally different from that of a normal cell. This has implications on the way therapies are being considered. The quest to normalize the tumor acidity could be a good strategy. Author SummaryCancer cells metabolism focuses the interest of the cancer research community. Although this process is intensely studied experimentally, there exists very few theoretical models that tackle this issue. One main reason is the extraordinary complexity of the metabolism that involves many inter-related regulation networks which makes it illusory to recreate computationally this complexity. In this study we propose a simplified model of the metabolism which focuses on the interrelation of the three main energetic metabolites that are oxygen, glucose and lactate with the aim to better understand the dynamic of the core system of the glycolysis-OXPHOS relationship. However simple, the model highlights the main rules that allow the cell to dynamically adapt its metabolism to its changing environment. It moreover allows to address this impact at the tissue scale. Simulations performed in a spheroid exhibit non-trivial spatial heterogeneity of the energy metabolism. It further reveals that the metabolic features that are commonly assigned to cancer cells are not necessarily due to cell intrinsic abnormality. They can emerge spontaneously because of the disregulated over-acidic environment.