Metabolic symbiosis between oxygenated and hypoxic tumour cells: an agent-based modelling study

Deregulated metabolism is one of the hallmarks of cancer. It is well-known that tumour cells tend to metabolize glucose via glycolysis even when oxygen is available and mitochondrial respiration is functional. However, the lower energy efficiency of aerobic glycolysis with respect to mitochondrial respiration makes this behaviour, namely the Warburg effect, counter-intuitive, although it has now been recognized as source of anabolic precursors. On the other hand, there is evidence that oxygenated tumour cells could be fuelled by exogenous lactate produced from glycolysis. We employed a multi-scale approach that integrates multi-agent modelling, diffusion-reaction, stoichiometric equations, and Boolean networks to study metabolic cooperation between hypoxic and oxygenated cells exposed to varying oxygen, nutrient, and inhibitor concentrations. The results show that the cooperation reduces the depletion of environmental glucose, resulting in an overall advantage of using aerobic glycolysis. In addition, the oxygen level was found to be decreased by symbiosis, promoting a further shift towards anaerobic glycolysis. However, the oxygenated and hypoxic populations may gradually reach quasi-equilibrium. A sensitivity analysis using Latin hypercube sampling and partial rank correlation shows that the symbiotic dynamics depends on properties of the specific cell such as the minimum glucose level needed for glycolysis. Our results suggest that strategies that block glucose transporters may be more effective to reduce tumour growth than those blocking lactate intake transporters.Metabolic alteration is one of the hallmarks of cancer and the well-known metabolic alteration of tumour cells is that cells prefer to do glycolysis over mitochondrial respiration even under well-oxygenated and functional mitochondrial conditions. On the other hand, there is evidence that oxygenated tumour cells could be fuelled by exogenous lactate produced from hypoxic glycolytic cells in which it can create a metabolic co-operation between oxygenated and hypoxic cell populations. This metabolic co-operation could allow tumour cells to economically share oxygen and glucose and promote tumour survival. Using a multi-scale approach combining multi-agent modelling, diffusion-reaction, stoichiometric equations, and Boolean networks representing cell regulatory mechanisms, we studied this metabolic co-operation between different populations of cells, exposed to a changing microenvironment. We predict that the tumour environmental glucose depletion is decreased while the oxygen depletion is increased by this metabolic symbiosis, promoting a further shift towards glycolysis. Our results also show that blocking glucose transporters could be more effective than blocking lactate intake transporters, because the former would disrupt both glycolysis and lactate production, drastically reducing tumour growth.