Overactive molecules team up to cause trouble


Luna J, Boni J, Cuatrecasas M, Bofill-De Ros X, Núñez-Manchón E, Gironella M, Vaquero EC, Arbones ML, de la Luna S, Fillat C.
“DYRK1A modulates c-MET in pancreatic ductal adenocarcinoma to drive tumour growth.”
Gut, pii: gutjnl-2018-316128. doi: 10.1136/gutjnl-2018-316128.

Pancreatic cancer is bad news. The disease is often detected late, because of a lack once it has spread aggressively through the body, and fewer than one in ten people will survive for five years after diagnosis – a figure that has barely changed over decades.

Now Susana de la Luna and her team in the Signalling and Gene Regulation group at the CRG may have discovered an important part of the puzzle of pancreatic cancer.

De la Luna’s research focuses on a group of five related proteins called dual-specificity tyrosine-regulated kinases (known as DYRKs), which send signals inside cells by sticking tiny chemical tags onto other proteins, either triggering them into action or switching them off.

DYRKs seem to be multipurpose molecules with a wide range of cellular functions, such as switching genes on, controlling cell proliferation, or modifying other proteins important for cells to do specific jobs within the body.

One in particular – DYRK1A – seems to be very important for the development of nerve cells in the brain. So it was a big surprise when it turned up in pancreatic cancer cells too.

“De la Luna was approached by Cristina Fillat – a leading pancreatic cancer researcher at the Institut d’Investigacions Biomèdiques August Pi i Sunyer (IDIBAPS), next door to the Hospital Clinic in the heart of Barcelona, who had noticed that DYRK1A was present at high levels in pancreatic tumour samples and not in healthy tissue.

“This was surprising to us because DYRK1A overexpression stops cells from proliferating, so its presence in cancer cells was quite unexpected,” de la Luna says. “So we really wanted to know what it was doing there.”

To find out, de la Luna and her team reduced or removed DYRK1A from pancreatic cancer cells growing in the lab, either using genetic engineering or a drug called harmine. Intriguingly, both treatments dramatically slowed down the growth of the cells, and also reduced their ability to move around and spread.

Moving from Petri dish to real life, Fillat’s group tested the same approach on mice with pancreatic cancer, significantly increasing survival time compared with untreated animals. Taking a closer look, the researchers discovered that the levels of two crucial cancer-driving signalling kinases – EGFR and MET – were also reduced along with DYRK1A.

Their findings, published in the journal Gut, suggest that the three proteins are teaming up inside cancer cells, forming a gang of ‘bad guys’ that take over the cellular controls and drive tumour growth.

“We realised that DYRK1A was joining together with these kinases, stabilising them so that they could send signals telling cancer cells to proliferate,” she says. “Reducing DYRK1A also reduces both EGFR and MET together – you get two for the price of one!”

Although harmine isn’t suitable for use in human patients, due to side effects, de la Luna and Fillat’s findings have raised a lot of excitement that drugs designed to block DYRK1A could be a useful new treatment for pancreatic cancer, perhaps in combination with EGFR- or MET-blocking therapies.

However, DYRK-blocking drugs won’t be suitable as a universal treatment for all types of cancer. Although DYRK1A drives the growth of pancreatic cancer and some other types of cancer, such as brain tumours, it might play a protective anti-cancer role in other types of cancer. This dual ability might seem confusing, but as de la Luna explains, it all depends on which other proteins have joined the team.

“We are working with the idea that this depends on the context and the proteins that DYRK1A is working with in that particular type of cell – sometimes this is good, and sometimes it’s bad,” she says.

“This highlights the importance of understanding the molecular makeup of a tumour before deciding on a treatment, so you know whether you’re dealing with a ‘good’ team held together by DYRK1A that is preventing tumour cell growth or a ‘bad’ team that is promoting it.”

The researchers are now studying pancreatic organoids – tiny ‘mini-pancreases’ grown in the lab from human tumour samples – to test out new drugs and combinations that might prove promising. There is a growing interest in DYRK inhibitors in academic labs and pharmaceutical companies, so de la Luna is hopeful that they will soon hit on some potential treatments to take forward into clinical trials.

Finally, there’s a pleasing symmetry to the fact that the strong, positive team formed by de la Luna and Fillat’s collaboration has helped to expose the bad team of proteins at work within pancreatic cancer cells.

“Neither of our labs could have done this on our own, and this joint study is much more than the sum of its parts,” de la Luna says. “Our groups were very different – ours is molecular, while Cristina’s has a focus on cancer therapies – but we have complementary perspectives on the problem. We’ve now applied for a shared grant to take forward our collaboration, so we’re excited to see what we will discover together in the future.”