Multi-omics data integration reveals novel drug targets in hepatocellular carcinoma
Christos Dimitrakopoulos, Sravanth K. Hindupur, Marco Colombi, Dritan Liko, Charlotte K.Y. Ng, Salvatore Piscuoglio, Jonas Behr, Ariane L. Moore, Jochen Singer, Hans‐Joachim Ruscheweyh, Matthias S. Matter, Dirk Mossmann, Luigi Terracciano, Michael N. Hall, Niko Beerenwinkel
Abstract
BACKGROUND: Genetic aberrations in hepatocellular carcinoma (HCC) are well known, but the functional consequences of such aberrations remain poorly understood. RESULTS: Here, we explored the effect of defined genetic changes on the transcriptome, proteome and phosphoproteome in twelve tumors from an mTOR-driven hepatocellular carcinoma mouse model. Using Network-based Integration of multi-omiCS data (NetICS), we detected 74 'mediators' that relay via molecular interactions the effects of genetic and miRNA expression changes. The detected mediators account for the effects of oncogenic mTOR signaling on the transcriptome, proteome and phosphoproteome. We confirmed the dysregulation of the mediators YAP1, GRB2, SIRT1, HDAC4 and LIS1 in human HCC. CONCLUSIONS: This study suggests that targeting pathways such as YAP1 or GRB2 signaling and pathways regulating global histone acetylation could be beneficial in treating HCC with hyperactive mTOR signaling.