Sleeping Beauty reveals childhood brain tumour’s secrets

Childhood cancer is no fairy story. It strikes over 30 children a week in the UK, and although survival rates have climbed dramatically over recent years – with more than eight in 10 children now beating the disease for at least five years compared to three in 10 in the 60s – there are still hundreds of young lives lost every year.

There are also big discrepancies between different types of childhood cancer. For example, 99 per cent of children with retinoblastoma will survive at least five years, and survival from some types of leukaemia and lymphoma stands at around 90 per cent or more. But figures from some other types of tumour don’t tell such positive stories.

Medulloblastoma is one of these. It’s a type of cancer called a primitive neurectodermal tumour, and accounts for up to a quarter of childhood brain tumours. Sadly, only around six in 10 children with the disease will survive for more than five years – although this can be up to eight in 10 for less aggressive tumours – and the treatments can take a brutal toll, as described in this moving blog post from one young patient’s mother.

The key to changing this outlook lies in research into the faulty genes that cause medulloblastoma to develop, grow and start spreading. Reading this genetic story will lead us to new, kinder treatments in the future, and an international research team – including scientists funded by us – have started turning the pages.

Once upon a time…

Our heroes in this story are part of an international collaboration bringing together researchers from Australia, Singapore, Canada, the US and the UK – including David Adams and Alistair Rust at the Wellcome Trust Sanger Institute, who are funded by Cancer Research UK.

Together, they’ve used a genetic engineering technique called Sleeping Beauty to track down some of the faulty genes that drive medulloblastoma, publishing their findings in the Proceedings of the National Academy of Sciences, or PNAS for short.

Back in 2012, our researchers in Cambridge used Sleeping Beauty to track down a new gene involved in pancreatic cancer. This time round, the international team has used a similar approach to pin down the culprits responsible for medulloblastoma.

Waking the Sleeping Beauty

As we’ve previously described, Sleeping Beauty is what’s known as a ‘jumping gene’, or transposon (read more on WiseGeek). Normally it stays put, ‘sleeping’ within the DNA of a cell. But researchers can ‘wake it up’, making it hop around in the genome. If Sleeping Beauty lands within another gene, then it can cause problems and stop that gene from working properly.

In this new research, the scientists studied mice carrying a fault in a gene called Patched (which regular readers may recognise from our story of the Hedgehog gene), making them more susceptible to developing medulloblastoma. These animals also carried Sleeping Beauty, quietly napping within the DNA of their cells.

Next, the researchers ‘woke up’ Sleeping Beauty in a small group of cells in the region of the brain where medulloblastoma usually develops, known as the granule neuron progenitors (GNPs) of the cerebellum. They then monitored the mice for signs of medulloblastoma, looking for animals that developed the disease even quicker than expected.

Sure enough, nearly seven in 10 of the mice they tested rapidly developed tumours, compared to three in 10 carrying a faulty Patched gene alone. In these animals, Sleeping Beauty had hopped into a gene involved in the disease –  together with the fault in Patched the animals already carried, this ‘double dose’ of genetic mistakes quickly led to cancer.

Tracking down the genes

The next step was to track down exactly where in the genome Sleeping Beauty had gone in each individual animal. Using gene sequencing technology, the scientists discovered more than 50 genes that had been disrupted in different mice.

Looking closer, they noticed an intriguing pattern. The gene faults fell into four distinct clusters, based on the kinds of biological pathways they worked in. These, in turn, mapped neatly onto four clusters of gene ‘signatures’ that had previously been discovered in medulloblastoma tumour samples from children.

One fault in particular, in a gene called Nfia, stood out as it was already known to be important in the development of GNPs – the brain cells that medulloblastoma develops from. Through lab experiments, the researchers were able to prove that Nfia usually acts as a type of gene known as a tumour suppressor, stopping cells from becoming cancerous and multiplying out of control. It makes a lethal combination alongside faulty Patched, rapidly driving the growth of medulloblastoma in GNPs.

Happily ever after?

So what does this all mean? For a start, the researchers have now collected a hatful of genes that are likely to play a role in the growth of medulloblastoma. Many of these could point towards future targets for new, urgently-needed therapies for children with the disease.

But new treatments for cancer must be developed and tested in the lab to make sure they’re safe and effective – you can’t just throw potentially dangerous and ineffective treatments at children without good evidence that they’re going to work. So researchers tend to use animal models to test out new approaches, before taking them into clinical trials.

At the moment, the animal models for medulloblastoma mimic a few specific subgroups of the disease, caused by a few individual gene faults, and don’t reflect the wide diversity of these tumours in patients. Because Sleeping Beauty can create tumours in animals that directly map onto all four groups of medulloblastomas in children, it’s a model that better reflects the real life situation. And having a better model that more accurately mirrors the complexities of the human disease should, in turn, be a big help to developing new treatments in the lab.

Although these results are important, they’re just one more step forward in our understanding of medulloblastoma, and there’s more work to be done to convert this knowledge into new cures.

Over the years, cancer research has already brought significant improvements in survival from childhood brain tumours. But we know there’s still a long way to go before every child is cured, and we’re not going to stop until we get there.

Kat

Reference
Genovesi L.A., Ng et al. (2013). Sleeping Beauty mutagenesis in a mouse medulloblastoma model defines networks that discriminate between human molecular subgroups, Proceedings of the National Academy of Sciences, 110 (46) E4325-E4334. DOI: 10.1073/pnas.1318639110