Pancreatic cancer changes its ‘diet’ to survive

Pancreatic cancer cells can change their ‘diet’ to keep growing, by switching from the sugar glucose to a back-up fuel called uridine, new research reveals.

The findings suggest that blocking the availability of uridine using new drugs could become a new treatment strategy for the most common and aggressive form of pancreatic cancer.

The researchers believe uridine could help fuel other cancers too – such as lung, stomach and brain cancer.

The study was led by scientists at The Institute of Cancer Research, London, and the University of Michigan in the US. It is published in Nature today (Wednesday) and was funded by Pancreatic Cancer UK, the Ian Harty Charitable Trust and the National Institutes of Health (NIH) in the US.

The molecule uridine is available around the body and is essential for a healthy metabolism. But researchers found that uridine, which is present in the tumour microenvironment, also serves as a food source for pancreatic cancer when glucose is scarce. Taking advantage of uridine in this way allows cancer cells to keep growing even when their usual food source is unavailable.

Using a technique known as a phenotypic microarray – which allows for testing of thousands of cell characteristics at once – researchers screened for nutrients used by pancreatic cancer cells over time, taking readouts every few minutes over three days.

They found that uridine is broken down by an enzyme known as uridine phosphorylase-1 (UPP1) to produce a different form of sugar, ribose, which can fuel cancer cells.

Knocking out the UPP1 gene in mice stopped pancreatic cancer cells from using uridine and halted tumour growth largely as a result.

These findings reveal a potential new strategy for treating pancreatic ductal adenocarcinoma, which exploits the fact that pancreatic cancers become metabolically dependent on uridine.

The team also looked at patient samples and found that high levels of UPP1 were linked to poor survival in people with pancreatic cancer, as well as other cancer types – suggesting that uridine may also help feed other cancers.

Researchers found that levels of UPP1 are boosted in the presence of KRAS-MAPK signalling, a type of cell signalling that promotes the growth of many cancer types, particularly pancreatic cancer. This led them to believe that drugs which block KRAS signalling might also block uridine availability, cutting off cancer’s emergency food supply.

There are no approved drugs for use in humans which block UPP1, but some KRAS inhibitors have already reached the clinic, and researchers will work to develop new UPP1 inhibitors.

Next, researchers are also planning further research to identify promising treatment strategies targeting uridine availability – either by using drugs that block KRAS or UPP1 on their own, or by combining them with immunotherapy.

Study co-leader Dr Anguraj Sadanandam, Team Leader in Systems and Precision Cancer Medicine at The Institute of Cancer Research, London, said:

“Cancer cells salvage anything available in their environment and use it for their own benefit. We have found that the deadliest form of pancreatic cancer can even change its diet in order to survive. Cancers can feed off a molecule known as uridine as an emergency back-up when they cannot access the glucose they normally rely on to stay alive.

“Next, we will explore ways to use uridine to monitor existing therapy responses in pancreatic cancer and hopefully develop new drugs targeting UPP1. We hope our research efforts will lead to new treatment strategies for people diagnosed with pancreatic cancer.”

Study co-leader Dr Costas Lyssiotis, Associate Professor in Molecular and Integrative Physiology at the University of Michigan and the Rogel Cancer Center in the US, said:

“These very exciting findings open up new avenues for treating a cancer that currently lacks effective treatment options – by targeting the fact that pancreatic cancer cells can become dependent on uridine for their growth and survival.”

Professor Kristian Helin, Chief Executive of The Institute of Cancer Research, London, said:

“People with pancreatic cancer often face a bleak prognosis so there is an urgent need for new advances to help treat this aggressive disease.

“We know cancer cells use different metabolic pathways to obtain nutrients that allow them to survive and keep growing. It is exciting that this new study has found that pancreatic cancers can switch their diets and may become dependent on a particular back-up fuel. We hope we can take advantage of this finding about the underlying biology of pancreatic cancers to find ways to treat the disease more effectively, including through use of existing drugs.”

Dr Chris Macdonald, Head of Research at Pancreatic Cancer UK, said:

“This is a very elegant piece of research, which demonstrates how we could use the cancer’s own growth tactics against it, to develop brand new and much needed treatments for people with pancreatic cancer. This work is hugely novel, potentially very impactful and really exciting. We are very hopeful that these findings could lead to new and improved treatments for pancreatic cancer in the future.”