Genome-scale modeling predicts metabolic differences between macrophage subtypes in colorectal cancer

Colorectal cancer (CRC) shows high incidence and mortality, partly due to the tumor microenvironment (TME), which is viewed as an active promoter of disease progression. Macrophages are among the most abundant cells in the TME. These immune cells are generally categorized as M1, with inflammatory and anti-cancer properties, or M2, which promote tumor proliferation and survival. Although the M1/M2 subclassification scheme is strongly influenced by metabolism, the metabolic divergence between the subtypes remains poorly understood. Therefore, we generated a suite of computational models that characterize the M1- and M2-specific metabolic states. Our models show key differences between the M1 and M2 metabolic networks and capabilities. We leverage the models to identify metabolic perturbations that cause the metabolic state of M2 macrophages to more closely resemble M1 cells. Overall, this work increases understanding of macrophage metabolism in CRC and elucidates strategies to promote the metabolic state of anti-tumor macrophages. [Display omitted] •RNAseq data from colorectal cancer patients inform computational metabolic analyses•Metabolites and reaction fluxes reveal divergent macrophage metabolic phenotypes•In silico knockdown of specific reactions shifts M2 metabolism to M1-like state•Genome-scale models advance understanding of macrophage metabolic activity Health informatics; Human genetics; Quantitative genetics; Cancer