Transcriptome profiles of cirrhotic liver treated with lysophosphatidic acid pathway inhibitors

Cirrhosis is a milieu that develops hepatocellular carcinoma (HCC), the second most lethal cancer worldwide. HCC prediction and prevention in cirrhosis are key unmet medical needs. Here we have established an HCC risk gene signature applicable to all major HCC etiologies: hepatitis B/C, alcohol, and non-alcoholic steatohepatitis. A transcriptome meta-analysis of >500 human cirrhotics revealed global regulatory gene modules driving HCC risk and lysophosphatidic acid pathway as a central chemoprevention target. Pharmacological inhibition of the pathway in vivo reduced tumors and reversed the gene signature, which was verified in organotypic ex vivo culture of patient-derived fibrotic liver tissues. These results demonstrate the utility of clinical organ transcriptome to enable a strategy, reverse-engineering precision cancer prevention. Cirrhosis-driven hepatocellular carcinoma (HCC) was induced in rats by weekly administration of low-dose diethylnitrosamine (low-dose DEN rat). HCC chemopreventive effects of lysophosphatidic acid (LPA) pathway inhibitors, AM063 (autotaxin [ATX] inhibitor) and AM095 (LPA receptor 1 [LPAR1] inhibitor), was examined.