Flicking the switch on cancer’s immaturity

Cancers are often born from just one cell that became faulty, developing into a tumour by copying itself over and over again.

But if you were to peer inside a tumour, you wouldn’t be faced with an army of cellular clones. Instead, tumours are made up of collections of cells that are surprisingly diverse.

So if a tumour comes from a single rogue cell, what’s responsible for the variety that can be seen with a microscope or hidden in a cell’s DNA? New research from Dr Paola Scaffidi, based at the Francis Crick Institute and funded by Cancer Research UK, is helping to answer this conundrum.

Published in the journal Science, Scaffidi’s latest study found that tweaks to a certain gene allowed cancer cells to divide without tiring themselves out, continually adding fuel to the growing tumour’s fire.

And crucially, the team was able to reverse this process in the lab, a discovery that could have implications for cancer treatment.

“Cancer cells naturally change as the tumour grows, which can affect the cells’ ability to divide,” says Scaffidi.

“Some of this is genetic, with the cells acquiring new genetic faults. But we’ve now shown that there is an additional layer of diversity which is non-genetic and, importantly, reversible.”

And if scientists can find a way to exploit this process, the discovery could potentially lead to new treatments.

Keeping genes under wrap

The team’s discovery began with a question: why do some cancer cells get stuck in a ‘youthful’ state and continue dividing, while others mature and tire out?

The troublesome ‘young’ cancer cells – so-called cancer stem cells – act as the tumour’s lifeline, offering a constant supply of cells to maintain the cancer’s growth.

And it’s these cells that have been the focus of Scaffidi’s work.

“I wanted to understand the processes behind the ability of these cells to keep growing,” she says.

I wanted to understand the processes behind the ability of these cells to keep growing

Dr Paola Scaffidi, Francis Crick Institute

And her team’s ultimate goal is to use this knowledge in the hunt for new treatments that could “make the cells become tired and stop dividing.”

In their latest study, the team looked for different genetic patterns in tumours from mice, comparing cells that divide continuously to those that don’t. Of the patterns that stood out, the team’s attention was drawn to a gene called H1.0, which was unusually quiet in the continually dividing cells.

The gene carries the recipe for a molecule called a histone, which acts like a spool for threads of DNA, keeping our genetic information packed in neat little bundles inside the cell. And the gene is usually highly active in tissues throughout the body, churning out lots of the histone molecule.

So why was the gene’s activity dampened down in those youthful cancer cells?

Loosening the knot

Interests piqued, the team looked at levels of gene activity in samples taken from patients with an aggressive type of brain tumour called glioblastoma multiforme, which characteristically contains lots of cancer stem cells that help the tumour grow rapidly.

They discovered that the activity of the gene was much lower in these cells compared with other tumour cells in the sample and normal brain cells. And when they looked at samples from several other common types of cancer – including prostate and breast cancer – the team found that gene activity levels weren’t even across the tumour. While in healthy cells from the same organ, the gene activity was stable across the tissue.

So if cells usually have the H1.0 gene switched on, what’s going on in these youthful cancer cells? It turns out that in these immature tumour cells, the H1.0 gene has a molecule tagged onto it which switches it off, blocking production of the H1.0 molecule.

The loss of the H1.0 protein causes DNA to unravel

“We’re not certain of how exactly this tag stops the H1.0 protein being made,” says Scaffidi.

“It may well be that the tag gets in the way of other molecules that are needed for the gene to be ‘read’ and turned into a protein.

“Or it could be that the tag alters the shape of the DNA, adding kinks or folds that physically block access to the gene.”

But what they do know is that a lack of the H1.0 molecule kicks off a series of changes that help the cells keep dividing. As its levels drop, bits of DNA begin to unravel like a tumbling ball of yarn, freeing up access to certain genes which then get switched on when they shouldn’t be.

Importantly, some of these genes are commonly faulty in cancer and in this case they act like an elixir of youth, keeping the cell in an immature state so that it can keep dividing.

Lost but not forgotten

Just as molecular tags can be added to bits of DNA, they can also be removed. This means that, at least in cancer cells, eternal youth might just be reversible.

In fact, when the team switched H1.0 back on in cancer cells in the lab, they were forced to mature and lost their ability to continue dividing – a discovery that could have implications for the development of new treatments.

“If we can find a way to reactivate H1.0 in cancer patients, then we might be able to stop tumour growth,” Scaffidi says.

“We’re looking for molecules which can boost H1.0 that are already used in patients, so we know they’re safe.

“We would also be restoring something that was already in the cell, rather than interfering with a particular process like many other drugs, so in theory the chances of side effects should be lower,” she adds.

And since the team found that having the gene switched off was linked with a poorer outlook in a number of different cancers, the ability to switch it back on again could potentially have benefits for multiple types of cancer.

“All cancers are different, which is why researchers are pursuing personalised medicine,” says Scaffidi. “But there are some basic principles that are shared between cancers, and reducing H1.0 levels may be one of these.”

Dr Duncan Odom, a Cancer Research UK scientist specialising in genetics, believes a link between H1.0 and multiple cancers could prove “interesting.”

“I think it’s cool that they found H1.0 appears to play a specialised role, especially in cancer biology,” he says. “But the work needs to be repeated in other labs to see if this is something that is truly widespread among cancers.”

So while the work is still in its infancy, by igniting further research it could potentially grow into something that one day impacts the lives of people affected by cancer.

Justine