Mechanistic Modeling of Gene Regulation and Metabolism Identifies Potential Targets for Hepatocellular Carcinoma.

Hepatocellular carcinoma (HCC) is the predominant form of liver cancer, and has long been among the top three cancers that cause the most deaths worldwide. Therapeutic options for HCC are limited due to the pronounced tumor heterogeneity. Thus, there is a critical need to study HCC from a systems point of view to discover effective therapeutic targets, such as through the systematic study of disease perturbation in both regulation and metabolism using a unified model. Such an integration makes sense for cancers as it links one of the dominant physiological features of cancers (growth, which is driven by metabolic networks) with the primary available omics data source, transcriptomics (which is systematically integrated with metabolism through the regulatory-metabolic network model). Here, we developed an integrated transcriptional regulatory-metabolic model for HCC molecular stratification and prediction of potential therapeutic targets. To predict transcription factors (TFs) and target genes affecting tumorigenesis, we used two algorithms to reconstruct the genome-scale transcriptional regulatory networks for HCC and normal liver tissue. which were then integrated with corresponding constraint-based metabolic models. Five key TFs affecting cancer cell growth were identified. They included the regulator CREB3L3, which has been associated with poor prognosis. Comprehensive personalized metabolic analysis based on models generated from data of liver HCC in The Cancer Genome Atlas revealed 18 genes essential for tumorigenesis in all three subtypes of patients stratified based on the non-negative matrix factorization method, and two other genes (ACADSB and CMPK1) that have been strongly correlated with lower overall survival subtype. Among these 20 genes, 11 are targeted by approved drugs for cancers or cancer related diseases, and 6 other genes have corresponding drugs being evaluated experimentally or investigationally. The remaining 3 genes represent potential targets. We also validated the stratification and prognosis results by independent dataset of Japan Hepatocellular carcinoma cohort samples from the International Cancer Genome Consortium database. In addition, microRNAs targeting key TFs and genes were also involved in established cancer related pathways. Taken together, the multi-scale regulatory-metabolic model provided a new approach to assess key mechanisms of HCC cell proliferation in a systems context and suggested potential targets.