In a study funded by FCF, scientists at the Princess Máxima Center for pediatric oncology and the Hubrecht Institute in the Netherlands have revealed new insights into the features of fibrolamellar carcinoma (FLC). Their findings, published this week in Nature Communications, may help in developing new drug therapies in the future.
The study, led by Dr. Benedetta Artegiani, research group leader at the Máxima Center, and Dr. Delilah Hendriks, researcher at the Hubrecht Institute, focused on creating novel organoid models of FLC. In the study, the team investigated the biological consequences of different mutations found in FLC and related cancers. According to Dr. Artegiani, “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’.”
The organoids they studied were engineered to contain the chimeric fusion gene DNAJB1-PRKACA – the hallmark of FLC. According to Dr. 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.”
That situation changed when they introduced another set of DNA alterations. According to 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.”
The researchers concluded that although mutations in the PKA genes are crucial to the formation of FLC, they may not completely explain the disease development. Dr. Hendriks commented, “These findings open the possibility to look for other factors to occur together with PKA mutations in FLC tumors.”
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