Sleeping Beauty

A ‘jumping gene’ called Sleeping Beauty has revealed new hope in understanding pancreatic cancer

Over recent decades we have made huge progress in survival for many types of cancer, including breast, bowel, testicular, and prostate cancer as well as childhood cancers.

But some types of cancer – including pancreatic, lung, and oesophageal cancers, as well as brain tumours – have remained stubbornly resistant to dedicated efforts of scientists and doctors to improve the situation.

We believe the key to beating cancer is through research – to know what causes the disease in the first place, what drives it to grow and spread, and how best to target it with different treatments. And it’s by working harder to understand these cancers with poor survival rates that we can change the outlook for patients.

Now scientists at our Cambridge Research Institute and the Wellcome Trust Sanger Institute have made an important step forward in understanding one of the most challenging forms of pancreatic cancer.

The researchers have hunted down a crucial gene involved in the disease and, publishing their results in the prestigious scientific journal Nature, have also revealed a potential way to target it.

Sleeping Beauty and jumping genes

Over recent years, scientists around the world have made great strides in understanding the faulty genes that lie at the heart of pancreatic cancer – whether these are inherited gene faults running in families or random mistakes that accumulate over an individual’s lifetime.  But there are still gaps in this knowledge, and we know there must be more genes out there.

To fill some of these gaps, Professor David Tuveson and his colleagues turned to mice carrying a faulty version of a gene called KRAS, which puts them at high risk of developing pancreatic cancer. Previous research has shown that this accurately reflects what’s going on in humans, providing a good lab model for studying the disease.

To hunt for new genes involved in pancreatic cancer, the researchers used a “jumping gene” (transposon), known as Sleeping Beauty, which can hop around within an organism’s DNA. When Sleeping Beauty lands within a gene or a region controlling a gene’s activity, it stops it from working properly. (If you want to know more about these fascinating jumping genes, read this article on Wisegeek.)

Under normal circumstances, mice with faulty KRAS genes develop pancreatic cancer relatively late in their lives. So the researchers looked for animals that developed the disease very quickly, where Sleeping Beauty must have ‘jumped’ into a gene that normally helps to protect against pancreatic cancer.

As expected, their experiment revealed a number of genes that have already been implicated in pancreatic cancer in humans, proving that their approach was working. But in over a hundred tumours from mice with ‘early’ cancer, they found that Sleeping Beauty had hopped into a gene called Usp9x, which hasn’t previously been pinpointed as playing a role in pancreatic cancer.

Looking closer, the researchers found that switching off Ups9x in mouse pancreatic cells (using a technique called RNAi) made them grow out of control and stopped them from dying when they should – key characteristics of cancer cells.  These experiments strongly suggested that the gene is involved in pancreatic cancer, so why hadn’t previous studies uncovered it?

A faulty switch, not a faulty gene

The answer came when the researchers turned to samples of pancreatic tumours taken from patients.  They found very low levels of Usp9x activity in samples from patients whose cancers had spread aggressively, but – surprisingly – didn’t find faults in the actual gene This initially seems a bit strange, but there are additional mechanisms other than being faulty that can switch a gene on or off.

The researchers had an inkling of what might be going on, and so turned next to pancreatic cancer cells growing in the lab. These also had low levels of Usp9x activity. But the scientists treated them with two particular drugs – azacytidine and trichostatin A. These drugs are special because they affect the molecular ‘switches’ (known as epigenetic marks) on DNA that tell a cell whether a gene is active or not. As they suspected, they found that the drugs slowed the growth of the cancer cells.

This confirmed that, in the case of Usp9x, the gene is active in healthy pancreas cells, helping to protect them against becoming cancerous. But if the ‘switches’ are flipped, then Usp9x is inactivated and the cells start growing out of control to form a tumour.

This helps to explain why Usp9x hadn’t turned up before, as most genetic screen are designed to look for faults in the genes themselves rather than these epigenetic ‘switches’

Where next?

Professor Tuveson thinks that Usp9x may be involved in around 15 per cent of pancreatic cancers. It’s also the first common tumour suppressor gene (a gene that protects against cancer) to be found in the disease. This is a significant step forward in our understanding of the molecular faults that drive pancreatic cancer.

Furthermore, the discovery suggests that drugs that alter the epigenetic ‘switches’ on genes may be useful for treating patients. A number of these are currently in clinical trials, and azacytidine is already used to treat some types of cancer. So there are good grounds for future trials investigating the effects of such ‘epigenetic modulator’ drugs in pancreatic cancer patients.

The bigger picture

After years of little progress, we’re now seeing some real movement in the field of pancreatic cancer research, and Professor Tuveson’s lab has been at the heart of much of this work. For example, last February, they published two papers looking at new drug combinations that might prove useful in treating the disease. And just a few weeks ago, they discovered that an enzyme-based drug might be able to break through pancreatic tumours’ tough outer coating, which could ultimately lead to a revolution in how we treat the disease.

Although all this research is still at a relatively early stage, this finding offers hope for future progress in beating pancreatic cancer – a disease that claims far too many lives, far too fast.

Kat

 Reference:

Pérez-Mancera, P. et al. (2012). The deubiquitinase USP9X suppresses pancreatic ductal adenocarcinoma Nature DOI: 10.1038/nature11114