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It may sound dramatic, but sometimes our bodies need to tell our cells to self destruct.
Known as apoptosis, this suicide mechanism is usually only triggered under certain circumstances – for example, when cells are no longer needed, there are too many of them, or a cell is doing something it shouldn’t. And this process occurs in all complex organisms.
But it’s a process that cancer cells manage to bypass – allowing them to keep multiplying. In fact, it’s so important in cancer, the ability to ignore instructions to self-destruct is considered a hallmark of the disease.
So reactivating this ‘self-destruct switch’ in cancer cells has been the dream for some cancer researchers for decades. But progress has been elusive – cancer cells are adept at finding ways to avoid following orders, especially orders that call for their own demise.
Nevertheless, researchers now know the identities of many of the key molecules involved in transmitting self-destruct signals.
Over the last few years, Professor Henning Walczak and his team at the UCL Cancer Institute have focused their attention on a particular set of suicide molecules, showing it’s possible to activate the cell death signal – centred on a molecule called TRAIL (short for TNF-related apoptosis-inducing ligand) – in lung cancer cells. And we’ve written about their previous work here.
Now, the same group has published a paper in the journal Cancer Cell, finding that particular genetic faults found inside cancer cells can actually subvert this self-destruct switch and instead encourage the cancer to spread.
So how does it work?
KRAS by name, crass by nature
Since the 1990s scientists have known that TRAIL signals could tell laboratory-grown tumour cells to commit suicide. But taking this concept out of the lab and into the clinic has proved fruitless: trials of drugs that flip these switches have yet to show any clinical benefit for patients.
Why? Professor Walczak and his colleagues wanted to find out.
Particularly puzzling was the fact that some cancers have more of the protein that kick-starts the signal – called the TRAIL receptor – on their surface. If TRAIL receptors are responsible for telling a cell to die, why would cancer cells need more of them?
The key to this puzzle turns out to involve a well-known cancer-causing gene fault: a mutation in a gene called KRAS.
KRAS acts as a molecular on/off switch that tells cells when to grow. But, in many cancers, faults in the gene leave it permanently switched on, constantly giving the green light for cells to grow.
Around one in five human cancers carry a fault in KRAS, but it is even more frequent in aggressive types of cancer – including just under a third of lung cancers and nearly all (95 per cent) of the most common type of pancreatic cancer, called pancreatic ductal adenocarcinoma.
Previously Professor Walczak and his team had found that some of the molecules necessary to carry out TRAIL’s ‘self destruct’ signal are dependent on KRAS being turned off.
But in cancers where KRAS is permanently switched on, it turns out that the cancer cell never receives the message to self-destruct. The faulty KRAS effectively sabotages the TRAIL signal, similar to cutting the wire from a switch to a light bulb. No matter how many times you flip the switch the light bulb won’t turn on.
So why would these cancer cells still make TRAIL receptors?
What Professor Walczak and his colleagues now discovered was quite remarkable: the faulty KRAS doesn’t just cut the wire to the light bulb – it actually redirects the signal to an entirely different, and previously unknown, set of signals.
“We found that when the TRAIL receptor was blocked from passing on the ‘self-destruct’ message, it instead activated a protein called Rac1,” Dr Silvia von Karstedt, lead researcher on the study, told us.
Quite the reverse of killing the cells, Rac1 then switches on a pathway that tells the cell to grow and spread.
“We did not expect that faulty KRAS was able to corrupt the self-destruct signal into a message encouraging the cancer to spread,” she said.
The researchers then tried to find out how TRAIL signalling could activate Rac1 in cancers with faulty KRAS. They were able to narrow it down to a part of the TRAIL receptor whose function wasn’t previously known – but demonstrated that it was critical to sending signals through this alternative pathway.
So what are the implications of this research?
Nuts and Bolts
Survival for both pancreatic and lung cancer are among the lowest of all cancers, and neither has improved much in the last 40 years.
The next step of this research will be to figure out precisely how TRAIL activates Rac1. Are there additional molecules involved or is it a direct interaction?
From there, they can find out whether blocking this alternative TRAIL signal is possible. And then work out whether drugs that do this would effectively flip tumours’ self destruct switch in patients who have cancer with faulty KRAS.
There’s a long way to go, but the more we understand the molecular wiring inside these cancers, the closer we’ll be to switching them off.
- von Karstedt, S., et al. (2015). Cancer Cell-Autonomous TRAIL-R Signaling Promotes KRAS-Driven Cancer Progression, Invasion, and Metastasis Cancer Cell, 27 (4), 561-573 DOI: 10.1016/j.ccell.2015.02.014
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