A Scalable, Open-Source Implementation of a Large-Scale Mechanistic Model for Single Cell Proliferation and Death Signaling

Abstract

Mechanistic models of how single cells respond to different perturbagens can help integrate disparate big data sets or predict response to varied drug combinations. However, the construction and simulation of such models have proved challenging. Our lab previously constructed one of the largest mechanistic models for single mammalian cell regulation of proliferation and death (774 species, 141 genes, 8 ligands, 2400 reactions). However, this, as many other large-scale models, was written using licensed software (MATLAB) with intricate programming structure, impeding alteration, expansion, and sharing. Here, we generated a new foundation for this model, which includes a python-based creation and simulation pipeline converting a few structured text files into an SBML-compatible format. This new open-source model (named SPARCED) is high-performance- and cloud-computing compatible and enables the study of virtual cell population responses at the single-cell level. We applied this new model to a subset of the LINCS MCF10A Data Cube, which observed that IFN{gamma} acts as an anti-proliferative factor, but the reasons why were unknown. After expanding the SPARCED model with an IFN{gamma} signaling module (to 950 species, 150 genes, 9 ligands, 2500 reactions), we ran stochastic single-cell simulations for two different putative crosstalk mechanisms and looked at the number of cycling cells in each case. Our model-based analysis suggested, and experiments support that these observations are better explained by IFN{gamma}-induced SOCS1 expression sequestering activated EGF receptors, thereby downregulating AKT activity, as opposed to direct IFN{gamma}-induced upregulation of p21 expression. This work forms a foundation for increased mechanistic model-based data integration on a single-cell level, an important building block for clinically predictive mechanistic models.