Fig. 3: Multiple mutations can create anti-apoptotic and pro-proliferative signalling.

A Abundance of MYC mRNA (left) and BCL2 (right) mRNA in simulations of wild-type (WT) (dash), an IKK-activating mutation (green), a BCL2-activating mutation (blue) and a MYC-activating mutation (orange) over time. Note that BCL2 mRNA is elevated at t = 0 as the model transitions from steady state phase (with enforced survival signal) to the dynamic phase (with dynamically-determined survival signal). B Changes in the abundance of Cdh1 protein at 6 h in the simulations from (A). Each simulated concentration is subtracted from the WT simulation and plotted on a log scale as either an increase or decrease in abundance. Note that both MYC and IKK activating mutations decrease Cdh1 indicating a more rapid transition from G1 to S phase. C Changes in the abundance of cCytoc (cytoplasmic cytochrome c, left) protein, and cSmac (cytoplasmic second mitochondria-derived activator of caspase, right) at 6 h in the simulations from (A). Each simulated concentration is subtracted from the WT simulation and plotted on a log scale as either an increase or decrease. Note that both BCL2 and IKK activating mutations decrease both cSmac and cCytoc indicating reduced apoptotic signalling. D Pipeline to incorporate mutational events from genetic sequencing to create patient-specific models. Example mutational mappings are shown, including the model parameters they modify. The full mapping is provided on in the Github repository (https://github.com/SiFTW/norrisEtAl/blob/main/muts2Params.csv). E Violin plot showing the concentration of Cdh1 in individual patient simulations created as shown in (D). Each abundance is standardised and displayed as a z-score. The region with below mean abundance of Cdh1 is highlighted in green and labelled as PP (pro-proliferative), with example patients highlighted that are within and outside this region. F Concentration of cSmac (left) and cCytoC (right) in individual patient simulations created as shown in (D). Each abundance is standardised and displayed as a z-score. The region with below mean abundance of each protein is highlighted in blue and labelled as PP (pro-proliferative), with example patients highlighted that are within and outside this region. Note that patient 1 (LS3593) is neither AA or PP, 2 (RICOVER_977) is only AA, 3 (RICOVER_126) is AAPP, and 4 (LS2305) is PP only.