New insights into liver cancer using organoids

New scientific insights into the features of fibrolamellar carcinoma (FLC), a rare type of childhood liver cancer

Their findings, by scientists from the Princess Máxima Center for pediatric oncology and Hubrecht Institute in the Netherlands, 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 tumour biology and biological consequences of different DNA changes.

It also uncovered the probable cell-of origin of one of the FLC tumour types.

Fibrolamellar carcinoma (FLC) is a type of liver cancer, mostly affecting adolescents and young adults.

Affecting one in five million people per year, FLC can certainly be called rare, but 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, researcher at the Hubrecht Institute, co-led 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 tumours.

This new information is needed to understand why the tumours arise, and to identify possible targets for better treatments for the disease.

Artegiani said: “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, [and] 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 [much] tumour tissue available for research. Thanks to this technique we were able to study this tumour type.”



Liver organoid models


Artegiani and Hendriks constructed the liver organoid models by modifying the protein kinase A (PKA) using CRISPR-Cas9.

PKA is a complex signalling 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.

The organoids contained the so-called mutant fusion gene DNAJB1-PRKACA. This DNA change is very often found in FLC tumours.

Hendriks said: “When reconstructing this mutation in the organoids, we saw that it indeed is able to mirror multiple features of the tumours we see in patients with FLC.

“Yet, this single mutation caused a rather mild effect on the overall cellular and molecular behaviour of the liver cells.”

The situation completely changed when they introduced another set of DNA changes, also found in patients with FLC.

Artegiani explained: “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 tumour aggressiveness.”

Next to this, the greatly enhanced transforming effect caused by the BAP1 and PRKAR2A DNA changes allows the cells to adapt to different environments. This possibly explains the uncontrolled growth of cells during FLC tumour formation.

The researchers concluded that although mutations in the PKA genes are crucial, they might not be sufficient for the development of FLC.

Hendriks said: “These findings open the possibility to look for other factors to occur together with PKA mutations in FLC tumours.

“This could be potentially exploited for possible future therapies for this form of childhood cancer.”


The cell-of-origin


To be able to develop new therapies, it is also essential to understand the biology of the cancer itself. One of the first steps is understanding from which cell type the cancer originates; the cell-of-origin.

Understanding the importance of specific gene faults in the initiation of FLC and the original cell could be crucial to understanding how the tumour could behave later on.

However, during the study, this turned out to be particularly difficult for FLC.

Artegiani advised: “The main cause is that these tumours present features of both hepatocytes and ductal cells, the two most important cells in the liver.

“Our organoids showed that the co-operation of PRKAR2A and BAP1 transformed an originally healthy hepatocyte into a ductal cell, with increased cancer stem cell features.

“This transformation of a cell type into another one is called transdifferentiation. This is a [particularly] interesting phenomenon that could happen in various tumours, and makes the identification of the cell-of-origin particularly difficult.

“However, with the use of our models, we were able to uncover the hepatocytes as the probable cell-of-origin.”

Altogether, this study greatly advances the understanding of FLC and paves the way for further research on how to better treat this rare cancer type.

The insights in genetic defects could potentially lead to new therapies for children with this disease.

And understanding the importance of specific gene faults in the initiation of FLC could in the future also help to better understand tumour heterogeneity and response between patients.

The research is published in Nature Communications.

Image 1: A culture of mini-livers

Image 2: Human mini-livers that present signs of both ductal cells (red) and cancer stem cells (green).

Both images: © Benedetta Artegiani / Princess Máxima Center for pediatric oncology.

Research Aether / Health Uncovered

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