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Miniature livers reveal behavior of common cancer-causing gene mutation

Liver tissue on scaffold
A mutated form of the BAP1 gene changes gene activity in a way that can promote liver cancer, but those changes can be reversed, Dutch researchers found. (H Rashidi 2018)

The BAP1 gene is mutated in up to 20% of liver cancer patients, but just how the abnormality promotes the growth of liver tumors is a big unknown. Researchers at Hubrecht Institute and Radboud University in the Netherlands have created a new model that’s helping to shed light on the role of BAP1 in liver cancer.

The team used miniature livers, or “organoids,” to study the function of mutated genes in liver cancer. They discovered that BAP1 mutations change cell behavior, making cancer more invasive. Those changes, however, can be reversed. They published their findings in the journal Cell Stem Cell.

The Dutch researchers started by taking organoids of healthy human livers and using the gene editing system CRISPR-Cas9 to alter them so BAP1 was mutated. The mutated organoids turned into solid, fast-growing masses similar to malignant tumors, whereas the non-mutated organoids stayed healthy.

Then they made liver organoids with four other commonly-mutated genes associated with cancer and transplanted them into mice. They didn’t become cancerous—unless the mutated form of BAP1 was also included. The addition of BAP1 led to the formation of malignant tumors.

The team used several different techniques to observe the organoids over time, including time-lapse imaging. They discovered 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.

Most importantly, the changes that mutated BAP1 causes to turn a benign mass into a malignant one can all be reversed, the researchers found.

“This underlines the importance of studying gene function in a relevant model, derived from the organ and the organism of interest,” said co-author Benedetta Artegiani, a post-doctoral student at the Hubrecht Institute, in a statement.

Improvements in the process of growing human organs could boost both research and therapies for common diseases. Last year, scientists at Cincinnati Children’s hospital described esophageal organoids that they grew entirely from stem cells. They’re using the organoids to study disorders of the gastrointestinal tract, including birth defects. The same team had already demonstrated the ability to grow liver tissue from stem cells.

BAP1 is already a target in oncology research. Epizyme’s lead pipeline asset, tazemetostat, is being tested in patients with several different types of cancer, including mesothelioma characterized by BAP1 loss-of-function. The FDA had put a partial clinical hold on trials of the drug last year, when concerns emerged about secondary malignancies, but it lifted the hold in September.

The Dutch researchers believe their liver organoids will be useful for studying other genes that may play a role in tumor formation. Healthy human organoids can be easily manipulated with CRISPR-Cas9, they noted, making it feasible to study how other genes may be contributing to liver cancer.