Unlocking the Mystery of Fibrolamellar Carcinoma Through Innovative Tech

Category Health

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Scientists at the Princess Máxima Center for pediatric oncology and Hubrecht Institute in the Netherlands have just published new findings on the features of fibrolamellar carcinoma (FLC), a rare type of childhood liver cancer. With the help of innovative technologies and mini liver organoids, researchers uncovered the probable cell-of-origin of one of FLC tumor types and the importance of changing different gene functions in the onset of FLC. This will be a valuable step towards developing better and more effective treatments in the future.

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Scientists of the Princess Máxima Center for pediatric oncology and Hubrecht Institute in the Netherlands have revealed new scientific insights into the features of fibrolamellar carcinoma (FLC), a rare type of childhood liver cancer. Their findings, published today in Nature Communications, may help in developing new drug therapies in the future.

Mini organs and the ‘molecular scissor’ system CRISPR-Cas9, allowed the researchers to better understand tumor biology and biological consequences of different DNA changes. It also uncovered the probable cell-of origin of one of the FLC tumor types.

FLC is the only type of childhood liver cancer that can be predicted to originate from a specific cell type (bile ducts)

Fibrolamellar carcinoma (FLC) is a type of liver cancer that mostly affects adolescents and young adults. Affecting one in 5 million people per year, fibrolamellar carcinoma can certainly be called rare. The survival rate is still low. In order to change this, new forms of treatment are highly needed.

Dr. Benedetta Artegiani, research group leader at the Princess Máxima Center for pediatric oncology, and Dr. Delilah Hendriks, a researcher at the Hubrecht Institute, co-lead a new study on fibrolamellar carcinoma by using innovative technologies. This allowed the researchers to better understand the different biological consequences of different mutations found in FLC and to study the biology of the tumors. This new information is needed to understand why the tumors arise, and to identify possible targets for better treatments for the disease. Artegiani says: "We used healthy human liver organoids, mini-livers grown in the lab, in our research. We developed a series of organoids, all with different DNA changes, mutations, that had previously been linked to FLC. We changed the genetic background of the organoids using the DNA modification technique CRISPR-Cas9, that works as a ‘molecular scissor’. Due to its rarity there is not many tumor tissue available for research. Thanks to this technique we were able to study this tumor type." .

Patients with FLC often have mutations in the protein kinase A (PKA) gene

Artegiani and Hendriks constructed the liver organoid models by modifying the protein kinase A (PKA) using CRISPR-Cas9. PKA is a complex signaling protein, able to switch other proteins on or off. This ‘protein switch’ is made up of different units, each of them encoded by a different gene. Changing the function of the different units through genetic changes seems to be crucial for the onset of FLC.

patient survival rate is still low, with little information from existing tissue samples

The organoids contained the so-called mutant fusion gene DNAJB1-PRKACA. This DNA change is very often found in FLC tumors. Hendriks: "When reconstructing this mutation in the organoids, we saw that it indeed is able to mirror multiple features of the tumors we see in patients with FLC. Yet, this single mutation caused a rather mild effect on the overall cellular and molecular behavior of the liver cells." .

increased research helped uncover the probable cell-of-origin of one of the FLC tumor types

The situation completely changed when they introduced another set of DNA changes, also found in patients with FLC. Artegiani: "This second background not only contains a mutation in one of the PKA genes, PRKAR2A, but also in an additional gene called BAP1. In this case, the organoids presented features typical of an aggressive cancer. This suggests that different genetic FLC backgrounds lead to different degrees of tumor aggressiveness." Next to this, the greatly enhanced transforming effect caused by the BAP1 and PRKAR2A DNA changes allows the cel-of-origin of one of the FLC tumor types to be predicted.

CRISPR-Cas9 system, often referred to as the 'molecular scissor', was used to modify the genetic background of organoids

The current research tools and techniques developed by the Princess Máxima Center and Hubrecht Institute opens up possibilities to further investigate FLC, and better develop treatment therapies. Establishing a better understanding of the tumor is the first step.

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