Researchers with the Hubrecht Institute in Utrecht, Netherlands and Radboud University in Nijmegen, Netherlands, recently developed a human model using organoids to evaluate the function of specific genes commonly mutated in liver cancer. They identified how the BAP1 gene, which is often mutated in liver cancer, changes how cells behave, probably making them more likely to metastasize. They published their research in the journal Cell Stem Cell.
Organoids are three-dimensional tissue cultures derived from stem cells. Another way of saying that is, organoids are mini-organs used as models for studying disease and biological function.
Although organoids are commonly used in research, they have typically been used in cancer research by comparing organoids grown from health organs to organoids grown from tumors. However, this isn’t a good way to study the function and role of specific genes that are already mutated in cancer.
The research group created a new model, growing organoids from healthy human liver and genetically modifying them using CRISPR/Cas9 gene editing to study how the changes affect tumor formation.
“Studying the function of such mutations in tumor formation is especially important in liver cancer,” stated Benedetta Artegiani, one of the researchers, “since it is a very heterogeneous type of cancer: a wide variety of mutations in different genes are found in different patients.”
The BAP1 gene is mutated in about 15% to 20% of liver cancers. The BAP1 enzyme is a tumor suppressor, and it’s not the only one involved in cholangiocarcinoma. However, its actual function wasn’t known. In their research, the team discovered that the organoids with BAP1 mutations were very different than in the healthy organoids. In the mutated organoids, they grew faster into solid masses, had more motility and fused with other organoids—similar to metastases.
The researchers also were able to reverse the morphology and behavior of the organoids by adding normal BAP1. The team developed organoids with mutations in four genes commonly mutated in liver cancer and then a mutation in BAP1 was added. The four without BAP1 formed benign adenoma when transplanted into mice. However, those receiving BAP1 formed malignant tumors known as cholangiocarcinoma.
Using a variety of techniques, they found that the BAP1 mutations affect which genes are active in the organoids, and the gene activity can be reversed. The conclusion is that mutations in BAP1 play a significant role in transitioning liver cancers from benign to malignant.
“These changes may depend on the cell type in which BAP1 is mutated,” stated Artegiani, “which may explain why the previously described functions of BAP1 differ between different types of cells. This underlines the importance of studying gene function in a relevant model, derived from the organ and the organism of interest.”
Part of what the researchers found was that BAP1 controls the expression of “junctional and cytoskeleton components by regulating chromatin accessibility,” the authors wrote.
Additional researchers from Maastricht University, the Netherlands Cancer Institute, The Princess Maxima Center for Pediatric Oncology, and Shandong University (China) were involved in the research.