Using Organoids to Study Liver Tumor Formation

In a study published today in Cell Stem Cell, researchers have developed a model using human organoids (miniature lab-grown organs) to study the function of specific genes that are mutated in liver cancer. They found that mutations in BAP1, a gene commonly mutated in liver cancer, changes the characteristics of the cells—making them more likely to be invasive.

The researchers developed a new model in which they genetically alter organoids from the healthy human liver using CRISPR/Cas9. The new model allowed them to study how genetic alteration influences tumor formation.

“Studying the function of such mutations in tumor formation is especially important in liver cancer, since it is a very heterogeneous type of cancer: a wide variety of mutations in different genes are found in different patients,” says first author Benedetta Artegiani of the Hubrecht Institute. Until now, the function of many of these genes in tumor development was unknown.

The researchers used their new model to study the function of BAP1, a gene that is mutated in approximately 15–20% of liver cancer patients. They found that organoids in which BAP1 was mutated had very different characteristics compared to the healthy organoids: They turned into solid masses that grew faster, were more motile, and fused with other organoids. When normal BAP1 was added to the organoids, these changes were reversed.

In addition, the researchers made organoids with mutations in four other genes that are often mutated in liver cancer. These organoids only formed benign adenoma when transplanted into mice. But if a BAP1 mutation was also added, the organoids formed malignant tumors.

By combining different approaches—microscopy, time-lapse imaging, and ‘multi-omics’ (RNA, DNA, and protein-based) techniques—the researchers dug into the mechanisms through which a mutation in BAP1 can affect tumor development. They found that mutating BAP1 changes which genes are active in the organoids and that these changes in gene activity can be reversed.

“These changes may depend on the cell type in which BAP1 is mutated, which may explain why the previously described functions of BAP1 differ between different types of cells,” Artegiani says. “This underlines the importance of studying gene function in a relevant model, derived from the organ and the organism of interest.”