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Scientists Reveal Fuel Source for Pancreatic Cancer Cell Growth

Scientists has revealed how pancreatic cancer cells can change their fuel source to keep growing, offering hope for new treatments to tackle the deadly disease.

There are around 10,500 new pancreatic cancer cases in the UK every year, which equates to 29 every day, according to Cancer Research UK.

Pancreatic ductal adenocarcinoma (PDA) is a lethal disease notoriously resistant to therapy. Pancreatic cancer survival had not shown much improvement in the last 50 years in the UK, Cancer Research UK pointed out, with only 5% of those people diagnosed with pancreatic cancer in England surviving their disease for 10 years or more.

"Cancer cells salvage anything available in their environment and use it for their own benefit," said Dr Anguraj Sadanandam, team leader in systems and precision cancer medicine at the the Institute of Cancer Research (ICR) in London, and study co-leader. 

However, the spectrum of metabolites used as nutrients by this cancer remained largely unknown. Led by scientists at the ICR in London and the University of Michigan in the US, the new study, published in Nature, revealed how pancreatic cancer cells in mice switched their fuel source in order to continue growing.

"We have found that the deadliest form of pancreatic cancer can even change its diet in order to survive," Dr Sadanandam said. 

Cancer Cells Switch to 'Emergency' Fuel Source to Survive

The authors explained that the cancer cells switched from glucose to a "back-up" fuel called uridine, using this as "emergency fuel", when they cannot access the glucose they normally rely on to stay alive. The molecule uridine is available around the body and is essential for a healthy metabolism. It is also present in the tumour microenvironment and served as a food source for pancreatic cancer when glucose was scarce, the authors explained.

"Taking advantage of uridine in this way allows cancer cells to keep growing even when their usual food source is unavailable," they highlighted.

For their study, the scientists used a technique called phenotypic microarray. This allowed the testing of thousands of cell characteristics at once. They screened for nutrients used by pancreatic cancer cells over time, taking readouts every few minutes over 3 days. They found that uridine is broken down by the enzyme uridine phosphorylase-1 (UPP1) to produce ribose, which could 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," they highlighted.

In PDA, UPP1 is regulated by KRAS-MAPK signalling and augmented by nutrient availability, the authors explained. Tumours consistently expressed high UPP1 compared to non-tumoral tissues, they stressed, and UPP1 expression correlated with "poor" survival in patient cohorts. They demonstrated that uridine-derived ribose is actively catabolised in tumours. 

Other Cancers May Use Same Emergency Fuel

The scientists found that uridine utilisation was an important compensatory metabolic process in nutrient-deprived PDA cells, which suggested a novel metabolic axis for PDA therapy. This offered a potential new strategy for treating PDA that exploited the fact that pancreatic cancers became metabolically dependent on uridine, they said.

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, such as lung, stomach, and brain cancer.

"UPP1 deletion restricted the ability of PDA cells to use uridine and blunted tumour growth in immunocompetent mouse models," they highlighted. 

Researchers found that levels of UPP1 were 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.

"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," they said.

Future Treatment Hopes

Professor Kristian Helin, chief executive of the ICR underlined that people with pancreatic cancer often faced a "bleak prognosis", so there was an urgent need for new advances to help treat the aggressive disease. 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.

Study co-leader Dr Costas Lyssiotis, associate professor in molecular and integrative physiology, University of Michigan, and the Rogel Cancer Center in the US, said that the findings were "very exciting", and he hoped they would "open up new avenues for treating a cancer that currently lacks effective treatment options".

"Next, we will explore ways to use uridine to monitor existing therapy responses in pancreatic cancer and hopefully develop new drugs targeting UPP1," said Dr Sadanandam.

Dr Chris Macdonald, head of research at Pancreatic Cancer UK, believed the study was a "very elegant" piece of research, and was "hugely novel, potentially very impactful and really exciting". It demonstrated how the cancer's own growth tactics could be "used against it to develop brand new and much needed" treatments for people with pancreatic cancer, he enthused.

The study was funded by Pancreatic Cancer UK, the Ian Harty Charitable Trust, and the National Institutes of Health (NIH) in the US.CAL has received consulting fees from Astellas Pharmaceuticals, Odyssey Therapeutics, and T-Knife Therapeutics, and is an inventor on patents pertaining to Kras-regulated metabolic pathways, redox control pathways in pancreatic cancer, and targeting the GOT1-pathway as a therapeutic approach. AS received grants from Merck, Pierre Fabre, and Bristol Myers Squibb, and is an inventor on patents on colorectal cancer classification with differential prognosis and personalised therapeutic responses as well as prognostic and treatment response prediction in gastric cancer.