Organoid models of paediatric liver cancer developed

Model livers, which contain cells that are genetically identical to tumour cells, have been developed to study a rare paediatric liver cancer.

Fibrolamellar carcinoma is a rare form of liver cancer affecting children and adolescents, and has limited treatment options. Researchers from the Netherlands used genome editing to create model livers, known as organoids, to mimic the disease.

Dr Benedetta Artegiani, research group leader at the Princess Máxima Centre for paediatric oncology, Utrecht, said: 'We used healthy human liver organoids, mini-livers grown in the lab, in our research. We developed a series of organoids, all with different DNA changes, mutations, that had previously been linked to fibrolamellar carcinoma.'

In collaboration with the organoid group at the Hubrecht Institute, Utrecht, liver organoid models were created using CRISPR/Cas9 genome editing. This approach was used to insert new DNA sequences known to be linked to this cancer into healthy liver cells, called hepatocytes.

Publishing their research in Nature Communications, the scientists constructed liver organoid models to mimic the behaviour of cancerous cells by modifying the protein kinase A (PKA) complex, which is a family of enzymes involved in cell signalling. This complex is made up of different units, each encoded by a different gene. Firstly, they mutated one of the PKA genes in healthy liver tissue, a change that is very often found in this cancer. However, they discovered that this mutation only had only a small effect on the behaviour of the cells.

Patients with this cancer also often have mutations in another gene, called BAP1. Hence, the scientists decided to introduce this change to their model. They discovered that this additional mutation caused healthy liver cells to behave like an aggressive cancer.

Dr Delilah Hendriks, co-lead researcher from the Hubrecht Institute concluded: 'These findings open the possibility to look for other factors to occur together with PKA mutations in fibrolamellar carcinoma tumours. This could be potentially exploited for possible future therapies for this form of childhood cancer'.

Only one in five million people are affected by fibrolamellar carcinoma, hence there is a lack of tumour tissue available for research. As a result, the disease is poorly understood and survival rates are low for these patients.

This study confirmed that mutations in one of the PKA genes and the BAP1 gene contributes to cancer cell growth and the development of fibrolamellar carcinoma in humans. The researchers did, however, acknowledge that other genes that have not yet been identified are also likely to contribute to cancer development in these patients. The study also identified the hepatocyte as the likely cell-of-origin, informing future studies of this cancer.