Organoid Models of Human Liver Cancers Derived from Tumor Needle Biopsies

Hepatocellular carcinoma (HCC) is the most common primary liver cancer and the second cause of cancer-related mortality worldwide. HCC mainly arises in livers with pre-existing underlying diseases including viral hepatitis, alcoholic liver disease and nonalcoholic steatohepatitis. The multikinase inhibitor Sorafenib is the only drug available for the treatment of advanced HCC. However, due to the different backgrounds and the resulting heterogeneity of tumors, its efficacy greatly varies between patients and is further limited due to adverse effects and the development of drug resistance. Current in vitro models to study HCC based on pre-existing cancer cell lines fail in recapitulating key features such as tumor architecture, cellular heterogeneity and cell-cell interactions. In this study we report the generation of long-term three-dimensional organoid cultures from tumor biopsies of HCC patients with different etiologies and tumor stages. We demonstrate that HCC organoids retain the morphology and histological grading of the primary tumor as well as the expression pattern of HCC tumor markers. Moreover, whole exome sequencing analyses demonstrated that HCC organoids preserve the genetic heterogeneity present in their original tumors. Finally, in proof-of-principle studies we show that liver cancer organoids can be used to test sensitivity to Sorafenib. In conclusion, organoid models can be derived from needle biopsies of liver cancers, preserve the original tumor characteristics and provide a novel tool for developing tailored therapies urgently needed for a frequent malignancy with limited treatment options.EGA study EGAS00001003115