Liver Model Shows Function of Mutated Liver Genes

Organoids, or miniature livers, revealed how BAP1 mutations change cell behavior.


Miniature livers known as organoids have been used by researchers at Hubrecht Institute and Radboud University in the Netherlands to investigate the impact of genetic mutations in the liver on the development of liver cancer.


The scientists first took organoids from healthy human livers and caused mutation of the BAP1 gene using CRISPR gene-editing technology. They then looked to see how the organoids changed. Notably, they turned into solid, fast-growing masses similar to malignant tumors, while organoids without the mutation stayed healthy.


Four other mutations linked to liver cancer were then introduced into genes in other organoids. Interestingly, these organoids did not become cancerous unless the BAP1 gene was also altered.


The changes in the organoids were observed using several different analytical techniques, including time-lapse imaging. Through these analyses, it was determined that the mutated form of BAP1 changes which genes are active — but that the function of the mutated gene may be different in different types of cells.


In addition, the changed caused by the presence of the mutated BAP1 gene were found to be reversible.


BAP1 is the target of a drug being developed by the company Epizyme. Its candidate tazemetostat is being investigated for the treatment of several types of cancer, including mesothelioma. The researchers in the Netherlands believe that organoids will be useful for studying other genetic diseases and the roles played by different genes in the development of cancerous tumors.



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