Human primary liver cancer–derived organoid cultures for disease modeling and drug screening

• Published in: Nature Medicine Vol. 23; no. 12; pp. 1424 - 1435
• Main Authors: Broutier, Laura, Mastrogiovanni, Gianmarco, Verstegen, Monique MA, Francies, Hayley E, Gavarró, Lena Morrill, Bradshaw, Charles R, Allen, George E, Arnes-Benito, Robert, Sidorova, Olga, Gaspersz, Marcia P, Georgakopoulos, Nikitas, Koo, Bon-Kyoung, Dietmann, Sabine, Davies, Susan E, Praseedom, Raaj K, Lieshout, Ruby, IJzermans, Jan N M, Wigmore, Stephen J, Saeb-Parsy, Kourosh, Garnett, Mathew J, van der Laan, Luc JW, Huch, Meritxell
• Format: Journal Article Magazine Article
• Language: English
• Published: New York Nature Publishing Group US 01-12-2017; Nature Publishing Group
• Subjects: 13; 13/106; 38/23; 38/39; 631/136/1425; 631/532/2441; 631/67/70; Animals; Antineoplastic Agents - isolation & purification; Antineoplastic Agents - therapeutic use; Bile Duct Neoplasms - drug therapy; Bile Duct Neoplasms - genetics; Bile Duct Neoplasms - pathology; Biomarkers; Biomedical materials; Biomedicine; Cancer; Cancer Research; Carcinoma, Hepatocellular - drug therapy; Carcinoma, Hepatocellular - genetics; Carcinoma, Hepatocellular - pathology; Cell culture; Cell Proliferation; Chemical compounds; Cholangiocarcinoma; Cholangiocarcinoma - drug therapy; Cholangiocarcinoma - genetics; Cholangiocarcinoma - pathology; Development and progression; Drug screening; Drug Screening Assays, Antitumor - methods; Gene expression; Gene Expression Regulation, Neoplastic; Hepatocellular carcinoma; Hepatocytes; Humans; In vivo methods and tests; Infectious Diseases; Life Sciences; Liver; Liver cancer; Liver Neoplasms - drug therapy; Liver Neoplasms - genetics; Liver Neoplasms - pathology; Male; Metabolic Diseases; Metastases; Mice; Mice, Inbred NOD; Mice, SCID; Molecular Medicine; Neurosciences; Organoids; Organoids - pathology; Pathophysiology; Pharmacology; Precision Medicine; Primary Cell Culture - methods; Propagation; Screening; Transcriptome; Tumor Cells, Cultured; Tumors; Utilities; Xenograft Model Antitumor Assays; Xenografts; United Kingdom
• ISSN: 1078-8956; 1546-170X; 1744-7933
• DOI: 10.1038/nm.4438

Tumor organoids derived from the most common subtypes of primary liver cancer recapitulate the histologic and molecular features of the tissues of origin, even after long-term culture. These
in vitro
models, as well as those for colorectal cancer reported in Crespo
et al.
in a previous issue, are amenable for drug screening and allow the identification of therapeutic approaches with potential for cancer treatment.
Human liver cancer research currently lacks
in vitro
models that can faithfully recapitulate the pathophysiology of the original tumor. We recently described a novel, near-physiological organoid culture system, wherein primary human healthy liver cells form long-term expanding organoids that retain liver tissue function and genetic stability. Here we extend this culture system to the propagation of primary liver cancer (PLC) organoids from three of the most common PLC subtypes: hepatocellular carcinoma (HCC), cholangiocarcinoma (CC) and combined HCC/CC (CHC) tumors. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumor, allowing for discrimination between different tumor tissues and subtypes, even after long-term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumorogenic potential, histological features and metastatic properties of PLC-derived organoids are preserved
in vivo
. PLC-derived organoids are amenable for biomarker identification and drug-screening testing and led to the identification of the ERK inhibitor SCH772984 as a potential therapeutic agent for primary liver cancer. We thus demonstrate the wide-ranging biomedical utilities of PLC-derived organoid models in furthering the understanding of liver cancer biology and in developing personalized-medicine approaches for the disease.