A Computational Framework for Prediction and Analysis of Cancer Signaling Dynamics from RNA Sequencing Data-Application to the ErbB Receptor Signaling Pathway.

Abstract

Simple SummaryTemporal signaling dynamics are important for controlling the fate decisions of mammalian cells. In this study, we developed BioMASS, a computational platform for prediction and analysis of signaling dynamics using RNA-sequencing gene expression data. We first constructed a detailed mechanistic model of early transcriptional regulation mediated by ErbB receptor signaling pathway. After training the model parameters against phosphoprotein time-course datasets obtained from breast cancer cell lines, the model successfully predicted signaling activities of another untrained cell line. The result indicates that the parameters of molecular interactions in these different cell types are not particularly unique to the cell type, and the expression levels of the components of the signaling network are sufficient to explain the complex dynamics of the networks. Our method can be further expanded to predict signaling activity from clinical gene expression data for in silico drug screening for personalized medicine.A current challenge in systems biology is to predict dynamic properties of cell behaviors from public information such as gene expression data. The temporal dynamics of signaling molecules is critical for mammalian cell commitment. We hypothesized that gene expression levels are tightly linked with and quantitatively control the dynamics of signaling networks regardless of the cell type. Based on this idea, we developed a computational method to predict the signaling dynamics from RNA sequencing (RNA-seq) gene expression data. We first constructed an ordinary differential equation model of ErbB receptor → c-Fos induction using a newly developed modeling platform BioMASS. The model was trained with kinetic parameters against multiple breast cancer cell lines using autologous RNA-seq data obtained from the Cancer Cell Line Encyclopedia (CCLE) as the initial values of the model components. After parameter optimization, the model proceeded to prediction in another untrained breast cancer cell line. As a result, the model learned the parameters from other cells and was able to accurately predict the dynamics of the untrained cells using only the gene expression data. Our study suggests that gene expression levels of components within the ErbB network, rather than rate constants, can explain the cell-specific signaling dynamics, therefore playing an important role in regulating cell fate.