A Tale of Two Genomes

27th April 2021

Efforts to elucidate how mutations in a cell's DNA cause cancer have overwhelmingly focused on the DNA within the nucleus, but a new study published Nature Metabolism highlights the exciting potential of also looking at the genome of the cell's energy factories: the mitochondrial genome.

Mitochondria shutterstock 396424405It's known that mitochondrial mutations can be found in cancer cells, but there has been little research into what they do or whether they have any effect on treatment response or how the cancer will progress.

To answer these questions, Dr Payam Gammage at the Beatson Institute collaborated with the Memorial Sloan Kettering Cancer Center in New York to collate and analyse the largest dataset so far of tumour samples that include mitochondrial genome data and the corresponding clinical outcomes of the patients.

By analysing this data from 344 patients with colorectal cancer, the researchers could match groups of mutations to the likelihood of survival. They found that, after controlling for other variables which affect cancer risk like age, the presence of mitochondrial mutations was associated with a 57 to 93% decreased risk of death from colorectal cancer, depending on the type of mitochondrial DNA mutation. The researchers hope that in the future, doctors could use this information to identify patients with more aggressive forms of bowel cancer so they can receive the most effective treatments.

The team also wanted to know how common mitochondrial mutations were in cancer more broadly. By looking at existing data from over 10,000 tumour samples across 23 cancer types to search for recurring mitochondrial mutations, they found that mitochondrial mutations were present in up to 60% of tumours, with 25 out of the 30 most commonly mutated genes across cancers being present in the mitochondrial genome.

These results indicate that mitochondrial mutations could play a role in survival beyond colorectal cancer. Further research is needed to understand the wider implications of mitochondrial mutations in different cancers, and to delve into the biological underpinnings behind it.

Gammage head 2020 067Payam, who co-led the study, said: "This new study shines a light on the impact of mitochondrial DNA mutations in cancer, which have been overlooked for decades. This discovery could have a huge impact on patient care, with potential for changes to suggested treatments and a patient's outlook based upon the mitochondrial DNA status of their cancer. However, further research will be necessary to move these discoveries from the lab to the clinic."

Dr Ed Reznik, co-lead author based at Memorial Sloan Kettering Cancer Center, said: "Using data hiding in plain sight, we have shown that a critical piece of the cell's machinery to make energy is quite often broken in cancers. It now begs the question of how these mutations within mitochondrial DNA might be exploited as drug targets."

Michelle Mitchell, chief executive of Cancer Research UK, said: "This work highlights just how much more there is to discover about the inner workings of cancer, and all those breakthroughs for people with cancer we have yet to unlock. An incredible amount of basic laboratory research like this is being carried out across our Centres and Institutes, which is so important for helping to drive forward these unchartered and pioneering areas of research."

The paper can be read here: Gorelick AN, Kim M, Chatila WK, La K, Hakimi AA, Berger MF, Taylor BS, Gammage PA, Reznik E. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. Nat Metab. 2021 Apr 8. doi: 10.1038/s42255-021-00378-8

Publication Highlights: April 2021

This month’s publications highlight the collaborative science that the Beatson regularly participates in both in the UK and around the world.

In research published in Nature Metabolism (Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA), Payam Gammage, together with colleagues at the Memorial Sloan Kettering Cancer Center in New York, found that mutations in mitochondrial DNA (mtDNA) increased the chances of survival for patients with bowel cancer. The researchers compiled the largest study of tumour samples to date that investigated the mitochondrial genome. Over 20 cancer types were investigated and more than half of the samples showed mutations within mtDNA. Using this information may aid more accurate prognosis and the development of new treatments in the future.

Beatson scientists David Stevenson, Colin Nixon, Douglas Strathdee and Owen Sansom joined a study, led by the CRUK Edinburgh Centre, on treatment resistance in colorectal cancer (CRC) [RAC1B modulates intestinal tumourigenesis via modulation of WNT and EGFR signalling pathways]. As reported in Nature Communications, they frequently detected RAC1B in late stage patient samples and linked its presence to aggressive CRC tumour types. Mechanistically RAC1B is required for the activation of EGFR signalling, and researchers are now translating their in vitro findings into clinical studies of EGFR inhibitors such as cetuximab with anti-RAC1B treatment for enhanced therapeutic success.

In a preprint available on bioRxiv Hing Leung, Arnaud Blomme and colleagues linked the THEM6 protein to drug resistance in advanced prostate cancer (THEM6-mediated lipid remodelling sustains stress resistance in cancer). THEM6 affected the lipid composition of cancer cells, thus altering a cell's stress response, such as that induced by anti-cancer therapy. As the scientists also observed that THEM6 created a 'tumour stimulating' environment in other hormone-dependent cancers, they propose it as a new therapeutic target beyond just prostate cancer.

Together with Karen Blyth, Alexei Vazquez, Dimitris Athineos and Matthias Pietzke, Institute of Cancer scientists investigated the metabolic role of immune-regulated IDO1 that is associated with aggressive pancreatic cancer (Immune-regulated IDO1-dependent tryptophan metabolism is source of one-carbon units for pancreatic cancer and stellate cells). They demonstrated a shift in preference towards tryptophan as a fuel for specialised metabolism that can aid cancer growth. The administration of anti-IOD1 therapy may enhance metabolically-targeted treatment strategies such as serine and glycine restriction but requires further research.

Liver cancer cases have doubled in Scotland

2nd April 2021

liver cancerA new study has shown that the rate of people dying from liver cancer in Scotland has doubled over the past two decades. The study also showed that over the same period Scotland has had the highest number of confirmed deaths from liver cancer per head of population out of any of the four UK nations.

Dr Tom Bird, group leader at the Beatson Institute and Honorary Consultant Hepatologist at Edinburgh Royal Infirmary, co-authored the paper. He said:

'Our analysis of this data is showing that liver cancer has become a much more common type of cancer in the UK.

'Whilst there are signs that survival with liver cancer is improving, it still claims far too many lives each year.'
Dr Tom Bird

Dr Bird continued: 'A major factor driving this long-term rise in cancer cases is fat within the liver related to obesity. We expect the trend to get worse, as the pandemic means that fewer people have come forward with symptoms and people's weights and drinking behaviour have been affected too. I see it every day, with more and more patients coming to me with later stages of the disease.

'But it's important to remember that obesity, and the liver diseases related to it, are both preventable and reversible. That's why we need new public health measures to tackle Scotland's weight problem and reduce the risk of developing cancer in the long-term.'

Professor Linda Bauld, Cancer Research UK's prevention expert, who is based at the University of Edinburgh, said: 'It's shocking that so many people in Scotland are being diagnosed and dying of liver cancer.

'It should worry us all that liver cancer rates have risen over the last few decades in Scotland. Sadly, it is preventable factors like being overweight or obese, smoking and excessive alcohol consumption that increase the risk.

liver cancer 3'When it comes to stemming the tide of disease caused by carrying too much weight, the next Scottish Government has the power to make a difference.

'The pandemic understandably stalled progress on new laws to ban the harmful supermarket junk food multibuy offers which encourage us to stock up on unhealthy items that provide no nutritional value. But it's clear from this study that action is still urgently needed to help us all lead healthier lives.

'This is why the next Scottish Government must bring forward legislation to ban supermarket price promotions on junk food at the earliest opportunity.'
Professor Linda Bauld

'It's vital we see action to help us all keep a healthier weight. The health of future generations depends on it.'

This research has also been covered in a news report on the Cancer Research UK website: Liver cancer rates in the UK are highest amongst men in Scotland

The study can be found here: Burton A, Tataru D, Driver RJ, Bird TG, Huws D, Wallace D, Cross TJS, Rowe IA, Alexander G, Marshall A. Primary liver cancer in the UK: Incidence, incidence-based mortality, and survival by subtype, sex, and nation. JHEP Rep. 2021;3:100232. 

Inhibiting apoptosis is the key function of MCL-1 in breast cancer

1st April 2021

MCL1A study - led by Kirsteen Campbell, Stephen Tait and Karen Blyth and funded by Breast Cancer Now - has shown that a protein called MCL-1 helps breast cancer cells survive and replicate by blocking apoptosis (cell death), and that tumours rely on it to grow more aggressively.

Importantly, a type of drug called BH3 mimetics target MCL-1 and could be used to restart apoptosis in breast cancer. What's more, this finding could have also implications for other cancers including leukaemia, those affecting the lung and glioblastoma.

For more details, see this article published in The Herald.

Reference: Campbell KJ, Mason SM, Winder ML, Willemsen RBE, Cloix C, Lawson H, Rooney N, Dhayade S, Sims AH, Blyth K, Tait SWG. Breast cancer dependence on MCL-1 is due to its canonical anti-apoptotic function. Cell Death Differ. 2021. Online ahead of print.

Christos Kiourtis wins JP Award

24th March 2021

christosMany congratulations to Christos Kiourtis who has been awarded the Institute's JP Award for best student presentation. Christos is a final-year PhD student in Dr Tom Bird's group, who work on liver disease and regeneration. Christos gave a fantastic talk on the role of the systemic effects of hepatocellular senescence. 

           Christos slide


The JP Award is named after the Institute's former director Dr John Paul (1922-1994), who established the Beatson Institute for Cancer Research as an independent research institute and moved it to our present location on the Garscube Estate in 1976.

International Women's Day 2021

8th March 2021

Today is International Women's Day! Since the International Day of Women and Girls in Science on 11th February, we've been highlighting many of our female scientists on twitter. Click 'read more' for a roundup!

Read more: International Women's Day 2021

Research

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