Genome Scale Modeling to Study the Metabolic Competition between Cells in the Tumor Microenvironment

SIMPLE SUMMARY: Immune and cancer cells compete for nutrients within the tumor microenvironment, leading to a metabolic battle between these cell populations. In this battle, tumor cells reprogram their metabolism for a high demand of building blocks and energy and to gain advantages over immune cells. To study these mechanisms, we require the quantification of metabolic fluxes, which can be estimated at the genome-scale, with constraint-based or kinetic modeling. ABSTRACT: The tumor’s physiology emerges from the dynamic interplay of numerous cell types, such as cancer cells, immune cells and stromal cells, within the tumor microenvironment. Immune and cancer cells compete for nutrients within the tumor microenvironment, leading to a metabolic battle between these cell populations. Tumor cells can reprogram their metabolism to meet the high demand of building blocks and ATP for proliferation, and to gain an advantage over the action of immune cells. The study of the metabolic reprogramming mechanisms underlying cancer requires the quantification of metabolic fluxes which can be estimated at the genome-scale with constraint-based or kinetic modeling. Constraint-based models use a set of linear constraints to simulate steady-state metabolic fluxes, whereas kinetic models can simulate both the transient behavior and steady-state values of cellular fluxes and concentrations. The integration of cell- or tissue-specific data enables the construction of context-specific models that reflect cell-type- or tissue-specific metabolic properties. While the available modeling frameworks enable limited modeling of the metabolic crosstalk between tumor and immune cells in the tumor stroma, future developments will likely involve new hybrid kinetic/stoichiometric formulations.