Parameter Identifiability and Sensitivity Analysis Predict Targets for Enhancement of STAT1 Activity in Pancreatic Cancer and Stellate Cells

The present work exemplifies how parameter identifiability analysis can be used to gain insights into differences in experimental systems and how uncertainty in parameter estimates can be handled. The case study, presented here, investigates interferon-gamma (IFNγ) induced STAT1 signalling in two cell types that play a key role in pancreatic cancer development: pancreatic stellate and cancer cells. IFNγ inhibits the growth for both types of cells and may be prototypic of agents that simultaneously hit cancer and stroma cells. We combined time-course experiments with mathematical modelling to focus on the common situation in which variations between profiles of experimental time series, from different cell types, are observed. To understand how biochemical reactions are causing the observed variations, we performed a parameter identifiability analysis. We successfully identified reactions that differ in pancreatic stellate cells and cancer cells, by comparing confidence intervals of parameter value estimates and the variability of model trajectories. Our analysis shows that useful information can also be obtained from nonidentifiable parameters. For the prediction of potential therapeutic targets we studied the consequences of uncertainty in the values of identifiable and nonidentifiable parameters. Interestingly, the sensitivity of model variables is robust against parameter variations and against differences between IFNγ induced STAT1 signalling in pancreatic stellate and cancer cells. This provides the basis for a prediction of therapeutic targets that are valid for both cell types. Author Summary: For the prediction of therapeutic targets and the design of therapies, it is important to study the same pathway across different cell types. This is particularly relevant for cancer research, where several cell types are involved in carcinogenesis. Pancreatic cancer is enhanced by activated pancreatic stellate cells. It would thus seem plausible for an effective therapy to hit stellate and cancer cells. The cytokine IFNγ is an inhibitor of proliferation in both cell types. Antiproliferative effects of IFNγ are mediated by STAT1 signalling. An important aspect is to determine those reactions that cause the differences in the initial increase of phosphorylated STAT1 and in the temporal profile of STAT1 nuclear accumulation between the two cell types. We examined this aspect by performing a parameter identifiability analysis for calibrated mathematical models. We calculated confidence intervals of the estimated parameter values and found that they provide insights into reactions underlying the differences. A key finding of sensitivity analysis elucidated that predicted targets for enhancement of STAT1 activity are robust against parameter uncertainty and moreover they are robust between the two cell types. Our case study therefore exemplified how identifiability and sensitivity analysis can provide a basis for the prediction of potential therapeutic targets.