Macrophages are an essential population in any tumor mass, where they can effectively perform pro- and anti-tumoral functions throughout the tissue. Despite there have been experimental and modeling frameworks to understand the molecular mechanisms associated with macrophage polarization, the functional role of intermediary stages in the tumor microenvironment still remains unclear. To contribute to this last field, we have reconstructed a regulatory network of macrophages and explore their phenotype space through Boolean dynamic modeling. Our reconstruction was based on transcriptional mechanisms, cytokine signaling, and microenvironmental tumor biology derived from experimental data. Our Boolean analysis was capable of recovering the functional identity of the previously reported M0, M1, M2b, and M2d macrophage phenotypes. Notably, our analysis suggests the existence of some new hybrid cell populations, which have not been experimentally described before. By creating a cell fate map, we recovered interesting plasticity patterns concomitant to macrophage polarization, allowing the in silico identification of control nodes to minimize malignant cell behavior. Expression patterns associated with developing transitional phenotypes from cell fate mapping closely mimic the composition of the tumor microenvironment and resemble its intercommunication with internal components. We created a theoretical genetically modified macrophage and used it to investigate plasticity properties and the potential to diminish malignant-related phenotypes and biological behavior. The stability of the resulting macrophage was then investigated in the context of the breast cancer microenvironment. This analysis highlighted the potential relevance of ‘silent’ hybrid macrophage phenotypes to the pathobiology of cancer and for the ultimate development of novel therapeutic interventions based on transitional macrophages as immunological targets. Our theoretical approach can serve as a guide to design experiments for unraveling the principles of the dual host-protective or -harmful antagonistic roles of transitional macrophages in tumor immunoediting and cancer cell fate decisions.
In this repository you cand simulate our analysis just by downloanding the file named BooleanModelsProtocol.R. We reccomend to download all of the .csv and .txt files to run the code without any errors.