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US grant supports new study into liver cancer

Fibrolamellar carcinoma is an extremely rare form of liver cancer that mainly affects adolescents and young adults. Symptoms usually occur at an advanced stage of the disease, when it’s more likely to have spread. A better understanding of the disease is key in finding new treatments. In a new study with US funding, Benedetta Artegiani plans to create organoid models of fibrolamellar carcinoma to look at the genetic processes driving the disease.

Affecting one in 5 million people per year, fibrolamellar carcinoma can certainly be called extremely rare. It can be told apart from other liver tumors by a distinct genetic fault, in which two genes are fused together. The resulting fusion protein is thought to drive the tumor’s growth. Recently, another gene called BAP1 has been found to play an important role in some patients with the disease.

Molecular scissors
In a new study, Benedetta Artegiani will apply her expertise in organoids to unravel the role of BAP1 in fibrolamellar carcinoma. ‘To study the genetic processes driving fibrolamellar carcinoma, it’s important to have accurate models of the disease in the lab,’ Artegiani explains. She plans to grow new organoids from the two most important types of liver cells. She will then use a gene-editing technique called CRISPR-Cas9, known as ‘molecular scissors’, to mimic the different DNA changes seen in patients. Artegiani: ‘We’ll then be able to assess how the different gene faults impact on the behavior of the cells, and how they change the molecular characteristics of the faulty cells.’

Wider genetic background
Artegiani will compare the BAP1 gene changes found in the new FLC-subtype with the previously known fusion of genes called DNAJB1 and PRKACA. In this way, she hopes to find out how these forms of the disease might be different or share similarities on a cellular and molecular level. Artegiani: ‘So far, the DNAJB1-PRKACA fusion is the only strong genetic link with fibrolamellar carcinoma that has been identified. But it’s not fully understood how this genetic fault causes the disease, and it doesn’t account for all cases.’

Possible targets for diagnosis and treatment
The recent finding that changes in BAP1 together with genes related to PRKACA can also drive fibrolamellar carcinoma offers a glimpse into the wider genetic background of the disease. ‘Hopefully, looking at how molecular mechanisms change in these different genetic backgrounds of fibrolamellar carcinoma could in future identify possible targets for new or better treatments for the disease,’ Artegiani says. She will also study the origin of the disease, aiming to identify in which cell type it starts. Understanding the importance of specific gene faults in the initiation of fibrolamellar carcinoma could in future help in diagnosing the disease.

International endeavor
Artegiani had previously looked at BAP1 gene faults in another type of liver cancer, called cholangiocarcinoma. That’s what drew the attention of the US-based Fibrolamellar Cancer Foundation, which is funding the new study. Artegiani: ‘Every form of childhood cancer is rare, which makes studying these diseases a distinctly international endeavor. I’m grateful for the foundation’s support, which gives us the chance to dive deeper into the mechanisms by which BAP1 drives fibrolamellar carcinoma and to help better understand this rare form of liver cancer in young people.’