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

Abstract

Human liver cancer research currently lacks in vitro models that faithfully recapitulate the pathophysiology of the original tumour. We recently described a novel, near-physiological organoid culture system, where 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) tumours. PLC-derived organoid cultures preserve the histological architecture, gene expression and genomic landscape of the original tumour, allowing discrimination between different tumour tissues and subtypes, even after long term expansion in culture in the same medium conditions. Xenograft studies demonstrate that the tumourogenic 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 lead 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.

Expansion of airway basal epithelial cells from primary human non‐small cell lung cancer tumors

“…Normal cells also outcompete tumor‐derived cells during cancer organoid derivation. Here, it has been possible to develop tumor‐specific media to select tumor organoids over normal colonic25 and hepatic26 epithelial organoids. For example, intestinal epithelial cells are dependent on exogenous Wnt in culture but constitutively active Wnt signaling, due to genomic aberrations in genes such as APC and/or CTNNB1 , often confers tumor cells with the ability to survive culture in Wnt‐free culture media.…”

“…Relevant biological differences might also exist between mitotic inactivation using irradiation4, 9 rather than mitomycin C, as used here. Alternatively, different tissue acquisition methods,9 feeder cell‐conditioned medium,10, 27 low oxygen,10 harsh tissue digestion protocols26 and/or initially serum‐starving cells6 might help to select tumor cells by inducing differentiation or apoptosis in normal epithelial cells.…”

Circulating tumor cell-derived organoids: Current challenges and promises in medical research and precision medicine

“…Organoids could be useful for testing drug efficacy, drug toxicity studies in liver organoids, or drug bioavailability studies in intestinal organoids [102,103]. In particular, CTC-derived models with relevant pathologies of patients could be a key link to screening specific drug/s [75,89,104].…”

Cancer research with a human touch

“…For instance, Meritxell Huch, a tissue-repair biologist at the University of Cambridge, UK, and her colleagues created liver-cancer organoids for drug screening 8 . This type of tumour can be grown in mice only about 20% of the time, but Huch achieved a success rate of nearly 80% -and the process worked about twice as quickly as with a patient-derived xenograft.…”