Table 1.
List of SPARCED model unit testing and comparisons to Bouhaddou2018 model.
| Descriptions of unit tests | Simulation type | Figure # | Original paper Figure # |
|---|---|---|---|
| Functional test to ensure the deterministic module is updated every 30 s with mRNA numbers generated by the stochastic module. | Hybrid | Supp. Fig. 2 | 2B |
| Simulated ligand-receptor cooperativity coefficients for the receptor tyrosine kinases match experimental observations (negative cooperativity: EGF, FGF, IGF, INS; no cooperativity: HGF, NRG1, and positive cooperativity: PDGF). | Deterministic | Supp. Fig. 3a | 3A + S3A |
| Activated EGF receptors internalize and peak ~30 min after ligand treatment. | Deterministic | Supp. Fig. 3b | S3B |
| EGF and insulin stimulation activates both ERK and AKT pathways. Dual stimulation with the two ligands induces prolonged AKT activation. | Deterministic | Supp. Fig. 4, 5 | 3B, C, D + S3C |
| Double and/or single stranded DNA damage activates p53 and DNA damage repair mechanisms represses its response. | Deterministic | Supp. Fig. 6a | 3E |
| Increasing DNA damage amount in single cells leads to higher number of activated p53 peaks. | Hybrid | Supp. Fig. 6b, c | 3F + S3E |
| Increasing simulated TRAIL dose decreases the time it takes to die for an average cell. | Deterministic | Supp. Fig. 7a, b | 3G |
| The fraction of surviving cells decreases as stimulated TRAIL dose increases. | Hybrid | Supp. Fig. 7c | 3H |
| Increasing ERK and AKT activity levels prolongs TRAIL induced time to death, whereas increasing PUMA and NOXA expression levels decreases the time it takes for cells to die. | Deterministic | Supp. Fig. 7d | 3I |
| Increasing Cyclin D mRNA levels induces proper cyclin-CDK complex progression and oscillations for cell cycle entry and progression. | Deterministic | Supp. Fig. 8a | 3J |
| Etoposide treatment induces cell cycle arrest and cell death. Cycling cells (with prior growth factor stimulation) show increased percentage of death to etoposide treatment, compared to non-cycling cells. | Hybrid | Fig. 3d, e | 4A, B, C |
| Inhibition of AKT and ERK pathways together synergistically increase cell death, in EGF and insulin stimulated cells. | Hybrid | Supp. Fig. 9 | 5A |
| ERK and AKT inhibition-induced cell death mechanisms are predominantly BIM dependent, not BAD dependent. | Hybrid | Supp. Fig. 10a | 5C |
| EGF and insulin cooperatively induce cell cycle entry, with insulin inducing very little cell cycle entry alone. | Hybrid | Supp. Fig. 10b | 6B |
| Activation of both ERK and AKT pathways is required for robust cell cycle entry. Time averaged ppERK and ppAKT levels correlate with Cyclin D levels. | Deterministic | Supp. Fig. 11 | 6E |
| The number of ribosomes within the cell doubles within 24 h. | Deterministic | Supp. Fig. 8b | S2D |
The SPARCED model passed each test depicted and recapitulated experimental and simulation observations reported by the Bouhaddou2018 model. Supp.: Supplementary.