Co-conspirator cell of aggressive paediatric cancer discovered

What makes recurrent adrenal tumours in children resistant to chemotherapy? Researchers at Amsterdam UMC have managed to shed some light on the problem.

What makes recurrent adrenal tumours in children resistant to chemotherapy? Researchers at Amsterdam UMC have discovered an anomalous doppelganger of the known tumour cell, thanks to a database in which researchers around the world have deposited ‘a huge amount’ of data.

Neuroblastoma is a form of cancer that occurs only in young children. Around thirty new patients develop the disease each year in the Netherlands, when the cells that produce adrenalin in the adrenal glands go awry. The treatment has barely improved over the past twenty years, says Rogier Versteeg, head of the Oncogenomics department at Amsterdam UMC. His department is trying to fathom why recurrent neuroblastomas are so aggressive, as the current chemotherapy works only for a time. In almost 60% of patients over the age of eighteen months the tumour returns within a few years. A new course of chemotherapy generally fails, so the young patient dies. ‘We have never understood why such a recurrent tumour cell suddenly becomes resistant,’ says Versteeg. ‘We always thought it was the same type of cell.’

International approach

The department in Amsterdam is working closely with neuroblastoma experts at academic hospitals in Heidelberg, Berlin and Ghent. The alliance has been made possible by ERACoSysMed, a network of which ZonMw is also a member. ‘This is a fantastic collaboration’, says Versteeg. ‘Together we have determined the DNA sequence and other features of hundreds of neuroblastomas. We now know for example that this tumour has few mutated genes, and that it is probably a matter of an imbalance in the activity of perhaps a thousand genes. This has to be tackled internationally, as it’s a relatively rare tumour. You need large groups of patients for research.’

Huge collection

One important tool that has allowed this collaboration to run smoothly is the R2 platform, a database with analysis software that the Oncogenetics department developed under the leadership of molecular biologist and bioinformatician Jan Koster. R2 allows cancer researchers all over the world to enter, analyse and interpret biological and clinical data on all kinds of tumours. Versteeg says it is used ‘an enormous amount’, so it now contains a huge collection of data on tumours. Not only about their DNA and RNA, but also their epigenetics: the histones that surround the DNA and determine whether or not it is activated. 

‘We hope we will eventually find a way to get rid of neuroblastomas for good.’

The joint study of neuroblastomas has led to an important breakthrough that may have something to do with the epigenetics of the tumour cells, Versteeg suspects. ‘We have discovered that neuroblastomas do not consist of a single type of tumour cell, as we thought, but of two kinds. They have the same DNA but look very different. So these are two different phenotypes that have different genes switched on and also have a different metabolism. One type, which we already knew of, has all the characteristics of a differentiated cell designed to secrete adrenalin. The other closely resembles embryonic precursor cells of these adrenergic cells. These primitive cells are unfortunately highly resistant to chemotherapy. We think that it is this cell type that survives in the body after treatment and returns in large numbers a few years later.’

Changing hats

Just why these primitive cells should be resistant Versteeg does not know. There are still a lot of unanswered questions. He also thinks it is strange that neuroblastoma cells ‘change hats’ so often, as he calls it. ‘Both types of cell can switch phenotype. That’s very strange. Normally, cells have a single direction of differentiation. In this case, however, they can go in both directions. It is not clear why this is so.’ What he does know is that the discovery of the aggressive primitive cells also provides an opportunity to develop a therapy that kills them.

Promising trials

The researchers have already found several new drug treatments that have an impact either on the primitive cells or on the differentiated cells. Again, this was achieved using the R2 database. Versteeg does not want to mention any names as yet, but the drugs work well in the lab. The first trials in mice were also positive, he says. ‘We add the substances to the tumour cells and immediately analyse the effect on all 20,000 genes. We can only do this using computer programmes – a method known as systems medicine. We hope this method will allow us to find a way of getting rid of neuroblastomas for good. But that will take a few years.’

About systems medicine

ERACoSysMed (ERA-network Cofunding of Systems Medicine) is a network that organises funding rounds to promote systems medicine in Europe. Systems medicine uses computer models and large quantities of clinical and biological data to enable more personalised care. Tailor-made treatment will be more effective and should have fewer side effects. To this end, ERACoSysMed encourages clinical practitioners, biologists, bioinformaticians, geneticists and pharmacologists to work together on an international basis. ZonMw has organised two calls for proposals, six awareness events and five workshops as part of ERACoSysMed.

Written by: John Ekkelboom