Breaking down cancer’s wall of resistance

“We really had hit a dead end.”

After countless hours of work in the lab, 2012 was a frustrating time for Professor Kairbaan Hodivala-Dilke – one of our leading researchers from the Barts Cancer Institute in London.

Her team had been trying to work out how tumours gather nutrients and oxygen from their very own ‘life-support system’ – tumour blood vessels – something vital in helping tumours grow and spread.

In particular, they were trying to alter these blood vessels – or perhaps even destroy them – cutting off a tumour’s life-support. But after investing serious time and effort to piece together this molecular puzzle, their experiments weren’t providing the answers they’d hoped for.

Two years later and they’re firing on all cylinders, thanks to a breakthrough involving a molecule called FAK – short for focal adhesion kinase. FAK is the major focus of a new study published last week by Professor Hodivala-Dilke and her team in the prestigious journal Nature.

But until recently, FAK had been the problem rather than being the solution, thwarting all attempts to stop cancer cells in their tracks.

So what led to this remarkable turn-around?

FAK alone is not enough

Professor Hodivala-Dilke explains that FAK is a “signalling molecule.”

FAK works like a telephone wire, relaying messages around a cell

“It’s a bit like a telephone wire, it takes signals from the nucleus out to the surface of the cell, and it takes signals from the outside of the cell into the nucleus.”

And by relaying these messages, FAK provides a way for the cell to respond to the world around it and the stresses it encounters.

“FAK is an important molecule and actually found in lots of different cell types including cancer cells,” says Professor Hodivala-Dilke.

And because of this role in tumour cells, research groups around the world have been looking for different ways to snip this telephone wire and cut off the communication that helps cancer cells grow.

This is particularly important since research has shown that signals involving FAK may lie at the heart of a tumour’s ability to grow a blood supply.

Much of this research has focused on the FAK molecules found in the cancer cells themselves, and not in the blood vessels that cultivate these tumours.

But when Professor Hodivala-Dilke’s team switched off FAK in tumours, it had no effect on the blood vessels, nor the delivery of oxygen to the tumours, nor the growth of the tumours. This was surprising.

The discovery went against the grain of all the previous research.

This called for a fresh approach, and Dr Bernardo Tavora – then a member of Professor Hodivala-Dilke’s research team – was on hand to provide it.

One paper to change it all

“Bernado read a paper from a lab in Boston,” she tells us.

“They had discovered that blood vessels aren’t just pipes that deliver oxygen and nutrients to the tumour, but that actually the cells in the blood vessels could talk to the tumour cells.”

This sparked Tavora to ask whether FAK present in the blood vessel cells was involved in this cross-talk.

“But at that time nobody knew how that talking was controlled,” says Professor Hodivala-Dilke.

They set out to test this, “and that’s where the really exciting data came through.”

It turns out that reading that single paper, two years ago, has taken their work in a new and exciting direction, one that would try and tackle a big problem in cancer treatment – resistance to chemotherapy.

Professor Hodivala-Dilke explains: “A problem in the clinic is that with some cancer types, in some people, certain types of chemotherapy show initial responses but then the cancer comes back, and we don’t always know why.”

FAK and the invisibility blanket

“If we just take away FAK from the blood vessels the tumour cells are left naked, and now the chemotherapy works better” – Professor Kairbaan Hodivala-Dilke

In their latest study, the team turned to experimental models of melanoma and lung cancer that respond poorly to chemotherapy and radiotherapy.

Using these models, they engineered blood vessel cells – rather than the tumour cells – to stop making FAK. Excitingly, the tumours now became highly sensitive to these treatments – in other words, in blood vessel cells, FAK seemed to be shielding the neighbouring tumour cells from treatments.

“So if we take away FAK from the blood vessel, we’ve realised that actually the cell doesn’t respond in the same way to these treatments.”

It turns out that FAK is helping the blood vessel cells produce a “cocktail of 20 or 25 different proteins known as cytokines,” which, as Professor Hodivala-Dilke puts it “are sort of throwing this invisibility blanket over the tumour cells.

“But if we just take away FAK from the blood vessels, they can’t do that anymore. So now these tumour cells are left naked and now the chemotherapy works better.”

Science across continents

There’s still more work to be done to see if FAK is performing the same protective role in people. But if it does, it suggests that specifically targeting FAK in the blood vessels – or other molecules it talks to – could help overcome drug resistance, something that would be of huge benefit to cancer patients.

But as well as these steps towards better treatment, the team’s findings highlight a new way of looking at cancer biology – one that focuses on the tumour, its blood vessels, and all the surrounding cells and tissues together.

As Professor Hodivala-Dilke puts it: “If I just give you sugar you’ll taste the sugar, and if I just give you flour you’ll taste flour, but if you put them all together to make a cake that’s the flavour you’re after.

“We need to think of the whole cake in one go I think.”

And it’s this – both in terms of looking at how tumours work, and also the nuts and bolts of carrying out research – that’s one of the most powerful messages to come out of this latest study.

Professor Hodivala-Dilke and her team have been collaborating for the last two years with the lab in Boston whose paper sparked these ideas. And she tells us that whether “across a cell or across the Atlantic,” communication can take you in surprisingly different directions.

And of the years of frustration before their breakthrough, she’s surprisingly sanguine.

“An experiment always gives you an answer, even if it’s the answer you don’t want.”

Nick

Reference

• Tavora, B, et al. (2014). Endothelial-cell FAK targeting sensitizes tumours to DNA-damaging therapy Nature DOI: 10.1038/nature13541

Telephone exchange image from Flickr and image of Professor Hodivala-Dilke courtesy of Marianne Baker, Barts Cancer Institute