Patient advocate Helen Matthews met with Owen Sansom to discuss the latest findings of the Cancer Grand Challenge project SPECIFICANCER, which aims to understand why mutations in certain genes only cause cancer in specific parts of the body.
Check out the video below to hear the conversation.
21st June 2021
Congratulations to or being shortlisted for the next Cancer Grand Challenges funding. f
Founded by Cancer Research UK and the US National Cancer Institute, Cancer Grand Challenges supports a community of diverse, global teams to come together, think differently and take on some of cancer’s toughest challenges.
David Lewis as part of the CANCAN team joins 10 others competing for a share of £80m to develop smarter, faster and bolder ways to solve some of cancer’s toughest problems. Winners will receive £20m and the freedom to unite above boundaries to unleash their scientific creativity.
Discover more: https://cancergrandchallenges.org/CANCAN
Androgen-deprivation therapy (ADT) is the standard of care for the treatment prostate cancer that cannot be removed by surgery. ADT is highly effective; however, many patients go on to relapse. Here, recent PhD graduate Rafael Sanchez Martinez and co-authors have used a proteomic analysis of prostate cancer models to reveal that distinct molecular mechanisms, include amino acid and fatty acid metabolism, affect the way tumours respond to ADT (SLFN5 regulates LAT1-mediated mTOR activation in castration-resistant prostate cancer). In particular, they found that a gene called Schlafen family member 5 (SLFN5) was involved in disease recurrence, and importantly, depletion of SLFN5 strongly inhibited the growth of tumours that had returned following ADT.
The vasculature is a major part of the gut. However, its role in the day-to-day maintenance of the gut is largely unexplored. Here (Dynamic adult tracheal plasticity drives stem cell adaptation to changes in intestinal homeostasis in Drosophila), postdoc Jessica Perochon and group leader Dr Julia Cordero, together with fellow authors, have used fruit flies to uncover a previously unrecognised crosstalk between stem cells in the gut and the fruit fly’s tracheal system (which is akin to our own vasculature). Importantly, this crosstalk is essential for gut regeneration.
Our Drug Discovery Unit uses ‘fragment-based drug design’ to identify fragments that could form the basis of new drugs to treat cancer. Alan Bilsland and others within the Drug Discovery Unit have used artificial intelligence and machine learning to generate a new fragment library (Automated Generation of Novel Fragments Using Screening Data, a Dual SMILES Autoencoder, Transfer Learning and Syntax Correction). They achieved this using SMILES (simplified molecular-input line-entry system) and chemical fingerprints from a set of 486,565 commercially available fragments.
Clonal haematopoiesis of indeterminate potential (CHIP) occurs when a subset of our blood stem cells gain mutations that increase their ‘fitness’, i.e. that allow them to outgrow their fellow stem cells. CHIP is associated with increased risk of developing leukaemia, as well as heart disease and stroke. By analysing the effects of mutations over a 12-year timespan, Kristina Kirschner and fellow authors have shown that gene-specific effects contribute to stem cell fitness (Longitudinal dynamics of clonal hematopoiesis identifies gene-specific fitness effects). Importantly, this holds potential for personalising the clinical management of people with CHIP in the future.
In April, we shared the story of a paper from Dr Payam Gammage, shedding light on the role of mitochondrial DNA mutations in cancer. Here, Payam explains in his own words the importance of mitochondria in cancer and the impact this could one day have on cancer care.
Mitochondria are in vogue, with devotees ranging from exercise physiologists and sports scientists to molecular biologists and clinicians all coalescing around these unusual organelles.
Given their position as a metabolic and energetic hub, as well as their central role in controlling cell death, mitochondria are also an area of focus for many cancer scientists. However, one essential facet of mitochondrial biology in cancer has remained underexplored; mitochondrial DNA (mtDNA).
A physically and heritably distinct piece of DNA that is passed down the generations through the maternal line, mtDNA exists only inside mitochondria. Recent work from my lab at the Cancer Research UK Beatson Institute, in collaboration with scientists at the Memorial Sloan Kettering Cancer Center in the US led by Dr Ed Reznik, has revealed the substantial impact mutations in mtDNA can have in cancer. Understanding this could offer up new indicators of disease prognosis and provide a new focus for future therapeutics.
At the molecular level, the components of mammalian mitochondria are assembled from viruses, bacteria and eukaryotes. As such, the organelle we see in human cells today is a trans-kingdom mixture that doesn’t fully resemble any of its ancestors.
Human mtDNA is a small genome, only 16,569 base pairs long. In keeping with its bacterial ancestry, mtDNA is also circular and multicopy – with hundreds to thousands of copies present in every cell. mtDNA is very genetically compact and encodes only 13 proteins, all of which are core subunits of the oxidative phosphorylation (OXPHOS) complexes.
These OXPHOS complexes, found only within mitochondria, are unique in human biology as they are the only cellular structures formed of proteins encoded by genes from the two separate genomes. The nuclear DNA provides around 90% of the required proteins for OXPHOS, and the mtDNA provides the remaining 10%.
Now, OXPHOS is not the only way to generate energy and building blocks for cells. A huge cancer research effort has gone into detailing the ways in which cancer cells can be rewired to survive and undergo rapid cell growth.
One of these metabolic changes is a much-discussed phenomenon known as the Warburg effect, where tumours generate large amounts of lactate by preferentially utilising glucose as a fuel source, despite being in conditions where their mitochondria could pick up the slack. Otto Warburg, and many since, have suggested that the altered metabolism associated with this effect, and other forms of metabolic dysfunction, are a driver of cancer initiation and progression. However, consensus on this view has never been reached in the cancer research community and these metabolic changes are often seen as a consequence of cancer rather than a potential cause.
In light of recent developments, this view may need to evolve. While anecdotal evidence of mtDNA mutations arising in tumours has been around for nearly two decades, in the last five years or so several studies using large scale sequencing data concluded that roughly 60% of tumours bear mutations of mtDNA (1,2,3). While these studies lacked statistical power and clinical insight, such clear links between a highly abundant and plausible source of mitochondrial dysfunction and cancer had never been made previously. There was a growing temptation amongst some to view these tumours as isolated groups of cells with both cancer and severe mitochondrial disease.
In a paper recently published in Nature Metabolism, my lab and colleagues from Memorial Sloan Kettering Cancer Center, detail the patterns underlying mtDNA mutations, the impacts these mutations have on tumours and the clinical implications of this in colorectal cancer (CRC) patients (4). In agreement with previous studies, we found that around 60% of tumours contain one or more mtDNA mutations. We also found highly recurrent mutations occurring across all tumours at specific stretches of DNA where a single DNA base is repeated, known as a homopolymer. This is significant because recurrence is an indicator of selective pressure – it implies the mutation confers an advantage to the cancer.
We also calculated a comparative mutation rate for all known cancer-associated genes, which included mtDNA genes. Surprisingly, this led us to the conclusion that mtDNA genes are among the most mutated genes in all cancer, with 25 of the top 30 most mutated genes being encoded in mtDNA. While comparing mtDNA and nuclear DNA does have its limitations – a relative understanding of these mutations can give us a sense of context and proportion when considering cancer genetics. Additionally, we showed that the mutational burden in mtDNA is unrelated to the mutational burden in the nucleus. This is important, because nuclear DNA mutational burden in many tumours is associated with their response to, among other things, immune-targeted therapies. It’s easy to see how mitochondrial mutational status could be harnessed to better allocate such treatments, if not allow development of mitochondria-targeted immunotherapies which may have advantages over current immunotherapy targets. Intriguingly, we saw that the burden of mutations in mtDNA was spread unevenly across the OXPHOS complexes. This hints at how tumours might harness specific forms of mitochondrial dysfunction, while struggling to survive with others and could inform future therapeutic approaches.
The mutations we detected in mtDNA are not arising late in tumour development but are present in stage 1 tumours at a comparable rate to stage 3 tumours. They also cause a distinct change in the way the nuclear DNA of the tumour cell is expressed. Increases in nuclear encoded OXPHOS genes and decreases in genes associated with innate immunity have been linked with diverse mtDNA mutations across nearly all cancers studied. Importantly, we found a substantial survival benefit for CRC patients whose tumours bear mtDNA mutations, with a decreased risk of death of 57-93% for the majority of those in this category.
This potentially holds significant immediate implications for CRC patient care, however, it also raises many other questions: will this impact be seen in other cancers or just CRC? What are the precise differences between mtDNA mutant vs non-mutant cancer, beyond the mtDNA changes? Do some approaches to therapy for these patients work better or worse because of this? Beyond these specific, immediate questions, do mtDNA mutations actually cause or predispose cells to becoming cancerous, and how has this been missed for so long?
A lot of clinical and laboratory work needs to be done to address these. However, some issues are easier to address. For example, in what now seems to be a major misstep, mtDNA has been actively excluded from analysis of sequenced tumours as a matter of course, mostly owing to technical issues that arise when mtDNA is included in the data. This is an unfortunate but likely reason for their relevance to cancer being overlooked.
For much of the history of cancer research, and with good reason, scientists have focused heavily on nuclear DNA. These efforts have led to cancer being seen by many as a disease of the genome, an understanding that our recent discoveries suggest should be broadened. Cancer: no longer a disease of the genome, but a disease of the genomes.
1. Ju et al. Origins and functional consequences of somatic mitochondrial DNA mutations in human cancer, 2014, eLife
2. Stewart et al. Simultaneous DNA and RNA mapping of somatic mitochondrial mutations across diverse human cancers, 2015, PLoS Genetics
3. Yuan et al. Comprehensive molecular characterization of mitochondrial genomes in human cancers, 2020, Nat. Genet.
4. Gorelick et al. Respiratory complex and tissue lineage drive recurrent mutations in tumour mtDNA. 2021, Nat Metab.
This article is reproduced from a Research Feature on Cancer Resesarch UK's Science Blog under a Creative Commons Attribution-NonCommercial-ShareAlike License.
13th May 2021
Máté Pálfy, Features & Reviews Editor at the Journal of Cell Science, caught up with Dr Julia Cordero to find out about her academic journey, from an undergraduate degree in Argentina, to a PhD in the United States, to a postdoc and starting her own group in Glasgow. Click here to read the interview.
Follow the link to read more about Julia's research: Local and Systemic Functions of the Intestine in Health and Disease
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.
It'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.
Payam, 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