A scalable, open-source implementation of a large-scale mechanistic model for single cell proliferation and death signaling.

Erdem C, Mutsuddy A, Bensman EM, Dodd WB, Saint-Antoine MM, Bouhaddou M, Blake RC, Gross SM, Heiser LM, Feltus FA, Birtwistle MR

Nat Commun 13 (1) 3555 [2022-06-21; online 2022-06-21]

Mechanistic models of how single cells respond to different perturbations 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. Here, we developed a python-based model creation and simulation pipeline that converts a few structured text files into an SBML standard and is high-performance- and cloud-computing ready. We applied this pipeline to our large-scale, mechanistic pan-cancer signaling model (named SPARCED) and demonstrate it by adding an IFNγ pathway submodel. We then investigated whether a putative crosstalk mechanism could be consistent with experimental observations from the LINCS MCF10A Data Cube that IFNγ acts as an anti-proliferative factor. The analyses suggested this observation can be explained by IFNγ-induced SOCS1 sequestering activated EGF receptors. This work forms a foundational recipe for increased mechanistic model-based data integration on a single-cell level, an important building block for clinically-predictive mechanistic models.

Cemal Erdem

DDLS Fellow

PubMed 35729113

DOI 10.1038/s41467-022-31138-1

Crossref 10.1038/s41467-022-31138-1

pmc: PMC9213456
pii: 10.1038/s41467-022-31138-1
figshare: 10.6084/m9.figshare.19658802.v1

Publications 9.5.0