Blocking the immune response to promote cancer progression: tumour lymph nodes as an accomplice to the crime?
Researchers from the Shields group at the MRC Cancer Unit have recently identified ways in which tumour-associated lymph nodes can change their behaviour following exposure to tumour-derived factors to exhibit features commonly associated with immune-suppression. Their study, entitled ‘Tumour-induced stromal reprogramming drives lymph node transformation’ was recently published in Nature Immunology.
Lymph nodes (LNs) function as a major immunological hub, which are essential for immune regulation and the generation of the appropriate immune response. However, lymph nodes are also the first site of spread for many types of cancer (that are not adequately ‘cleared’ by the immune system).It is becoming clear that LNs can generate a pro-tumour environment in response to tumour- derived signals, but how these responses are formed and what drives them is yet to be determined. The supporting stromal cell populations of lymph nodes are essential for their maintenance and physiological function. While studies have demonstrated the impact of tumour-derived factors on lymph node function (such as lymphangiogenesis), the contribution of stromal cells such as fibroblasts (fibroblastic reticular cells, FRCs) and the associated network they form has not been investigated.
This study is the first to demonstrate growth, structural remodelling and genetic (transcriptional) reprogramming of FRCS in tumour-draining lymph nodes (TDLNs) in response to tumour-derived factors even before tumour cells have spread. These alterations subsequently affected key immunological pathways, particularly decreases in guidance and survival cues, CCL21 and IL-7 respectively. This impacted not only the immune populations found within the LNs, but also their trafficking and localization once there. Combined, these have the potential to contribute to impaired function within these lymph nodes, promoting an immune-suppressive, pro-tumour environment.
“These findings demonstrate that tumours have to capacity to remotely modify TDLNs through aberrant stromal signalling, which affects their structure and function” says Dr Jacqui Shields, lead author on this study. “This study significantly enhances our understanding of the mechanisms whereby tumour-associated lymph nodes support a failed anti-tumour immune response and ultimately tumour progression. We hope to take this forward to determine if stromal remodelling can be predictive of metastasis in patients who have not yet presented with secondary disease”
Further information on research carried out by the Shields group can be found here.
A recently published paper from the Venkitaraman group has identified new potential avenues for the treatment of certain forms of cancer, which carry mutations affecting the KRAS gene.
Approximately 25% of all human cancers carry KRAS gene mutations. These include most pancreatic cancers, as well as many cancers of the lung and colon. It has recently been suggested that drugs that interfere with cell division (anti-mitotic drugs) selectively kill KRAS-mutant cancer cells. This idea is being tested in clinical trials.
Dr David Perera and Prof Ashok Venkitaraman have found that mutations in KRAS alone do not predict whether cancer cells will respond to anti-mitotic drugs. Instead, contrary to expectations, high expression of a second cancer-causing gene, c-MYC, cooperates with KRAS mutations to determine responsiveness. The study, entitled ‘Oncogenic KRAS triggers MAPK-dependent errors in mitosis and MYC-dependent sensitivity to anti-mitotic agents’ was recently published in Scientific Reports.
Dr David Perera, first author on this study, commented: "Our findings caution against the use of KRAS mutation alone as a biomarker predictive of response to anti-mitotic drugs such as paclitaxel, a drug which is currently used in the clinic for the treatment of several types of cancer. However, we suggest that high expression of a second cancer-causing gene, c-MYC, may cooperate with KRAS mutations to determine responsiveness.”
This study suggests that drugs targeting the cooperation between c-MYC and mutant KRAS could provide new approaches to treat pancreatic, lung or colon cancers. “Our study opens up new avenues to therapeutically target KRAS-mutant tumours and to stratify patients in ongoing clinical trials of anti-mitotic drugs.”
Further information on research carried out by the Venkitaraman group can be found here.
Allosteric Modulation of AURKA Kinase Activity via Disruption of its Protein-Protein Interaction with TPX2
The Venkitaraman group (in collaboration with researchers from the Department of Chemistry and Department of Biochemistry) have recently reported (in Scientific Reports) on the discovery of AurkinA, a novel inhibitor of AURKA (Aurora kinase A)-TPX2 interaction (Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2).
AURKA belongs to a family of Ser/Thr kinases, which are responsible for progression through mitotic cell division. It has been particularly implicated in many events surrounding transit through the G2 to M phases of the cell cycle and during mitotic cell division. Interaction with its protein partner, TPX2, promotes localisation to mircrotubules in the mitotic spindle and also modulates the catalytic activity of AURKA. Overexpression of AURKA is a common occurence in many cancer types, with efforts being made to therapeutically target its activity (using ATP-competitive inhibitors) in clinical trials. More recently, interest has shifted to allosteric inhibition of AURKA using compounds that interfere with interaction with TPX2.
This study demonstrated that AurkinA (the drug-like inhibitor of AURKA) disrupts the AURKA-TPX2 interaction and mislocalises the kinase from the mitotic spindle in cells. Unexpectedly, AurkinA binding to the Y-pocket (the pocket occupied by TPX2 in the AURKA-TPX2 complex) led to conformational alterations in AURKA that were distinct from those induced by TPX2 binding. These findings are thought to have implications for the chemical biology and selective therapeutic targeting of structurally related kinases.
Janeček M, Rossmann M, Sharma P, Emery E, Huggins DJ, Stockwell S, Stokes JE, Tan YS, Almeida EG, Hardwick B, Narvaez AJ, Hyvönen M, Spring D, Grahame McKenzie G, Venkitaraman AR. Allosteric modulation of AURKA kinase activity by a small-molecule inhibitor of its protein-protein interaction with TPX2. Scientific Reports. 2016 Jun 24;6:28528. doi: 10.1038/srep28528.
Further information on research carried out by the Venkitaraman group can be found here.
As part of the MRC Festival of Medical Research, the MRC Cancer Unit opened its doors to sixth-form students from a number of schools around Cambridge yesterday. Students were taken on tours of the Unit labs, where they completed a number of dry (computer-based) and wet lab-based activities based around the Units research. The lab tour was followed by a careers session, giving the students the unique opportunity to meet with staff from across the Unit.
The following video is a short extract of footage taken on the day. We hope this will give you some insight into the days events!
The first annual MRC Festival of Medical Research will run from June 18-26 2016. MRC-funded research establishments will be showcasing and discussing their work through events and activities planned at MRC-funded units, centres and institutes across the UK. Examples of some events include open days, public lectures/debates, activity days, workshops, interactive seminars and quizzes.
The objectives of the MRC festival are to:
- Engage the MRC community to increase understanding of the MRC's strategic aims and their own contribution to these
- Build trust in medical research by sharing MRC-funded research with audiences
- Increase awareness and understanding of the benefits of medical research to society
A complete list of MRC festival events can be found at this link.
A number of exciting events will be taking place around Cambridge to mark this festival. While some of these are by invitation, many are open to members of the public! A leaflet containing the full details of these events can be found here. For a list of events taking place around Cambridge please click here.
The MRC Cancer Unit will be hosting an Open Day for Sixth form school students. A number of local schools are scheduled to visit the Unit on June 22. The students will be taken on tours of the MRC Cancer Unit labs, where they will hear talks from our scientists and complete some hands-on activities based on the research techniques that we use on a regular basis. The tours will finish with a short Q and A careers session and the opportunity to meet with staff from across the MRC Cancer Unit.
Congratulations to Prof Rebecca Fitzgerald (MRC Cancer Unit) and her Upper GI team, who recently (5 May) received a Gastroenterology Team Award at the BMJ Awards 2016 (Cytosponge – find cancer early). The BMJ Awards are the UKs premier medical awards programme, recognising and celebrating the inspirational work done by doctors and their teams.
Competition for this year’s BMJ Awards, now in their eighth year, was very strong, with 320 entries. A rigorous selection process included presentations by shortlisted teams to a panel of judges that featured patient representatives for the first time. In collaboration with colleagues at Cambridge University Hospitals NHS Trust, the team at the MRC Cancer Unit developed a simple diagnostic test for oesophageal cancer, called the CytospongeTM, which the patient swallows, thereby avoiding the need for endoscopy.The biggest risk factor for cancer of the oesophagus is heartburn - acid reflux - but the vast majority of patients who go to their GPs with this complaint are not sent for endoscopy. The CytospongeTM is a simple pill-on-a-string, which is swallowed by the patient, remains in place for a few minutes for the gelatin-like coating to dissolve, and is then retrieved with only minor discomfort. The cells it has collected are tested for the presence of a protein, Trefoil factor 3 (TFF3), which is a marker for Barrett’s oesophagus, a common precursor of cancer. Once patients have been diagnosed with Barretts’, they can then undergo routine surveillance and preventative treatment. In a series of four studies, the CytospongeTM has proven itself suitable for use in primary care, accurate in diagnosing Barrett’s and acceptable to patients.
It has taken 10 years for this concept (CytospongeTM device and subsequent test) to be developed to clinical application, but it is now entering its final stages. The team are currently launching a final study in primary care (BEST3 trial) to ensure that the health economics add up. BEST3 will be a trial of over 9,000 patients, recruited across 176 GP surgeries spread throughout the UK. The surgeries will be randomised into two groups. One group will treat their patients with heartburn in the same way that they would usually. The other group will offer all their patients a CytospongeTM test to see whether they have Barrett's (a condition that can in some cases develop into cancer) as part of their clinical care. The trial will take three years to complete and should tell us whether this test is suitable for routine clinical use. Commenting on the trial, Prof Fitzgerald said: “Then we’ll take it to the National Institute for Health and Care Excellence and say, ‘Here it is.’” There is a risk that use of the test might generate such a need for follow-up that endoscopy departments would be flooded. “We’re aware of that, so now we’re working on going one step further”, Prof Fitzgerald says.
BEST3 will start recruitment in late summer. Members of the trial team will be available to talk about the trial for International Clinical Trials Day on Friday 20 May. There will be a stall promoting clinical trials, including the opportunity to take part in a mock 'chocolate trial' on the main concourse at Addenbrooke’s Hospital from 11.30-14.00.
- Photos used in the report are © Copyright Philippa Gedge Photography www.philippagedge.com.
New research carried out by the Fitzgerald group has identified two promising novel biomarkers for the early detection and treatment of oesophageal squamous cell carcinoma (OESCC). Oesophageal cancer (OC) is a disease with a poor prognosis. The 5-year survival rate for oesophageal cancer is less than 10% in developing countries, where more than 90% of these cancers as OESCC. There is therefore an urgent need to identify new biomarkers for OESCC, with the potential to enhance the accuracy of patient diagnosis for prevention and/or treatment.
Prof Fitzgeralds group used a publicly available cDNA dataset to identify 800 genes, which had altered expression in OESCC, relative to normal oesophagus. Validations of initial findings were carried out using qPCR (gene expression) and immunohistochemistry (tissue protein expression). Twenty genes were found to be significantly overexpressed in OESCC, relative to normal epithelium. Of these, TNFAIP3 and CHN1 showed significantly altered tissue expression across the sequence to OESCC.
This study therefore identified biomarkers (TNFAIP3 and CHN1) for oesophageal squamous dysplasia and OESCC. The next step would involve a clinical study to assess the efficacy of TNFAIP3 and CHN1 as diagnostic biomarkers for OESCC. These biomakers could also help in the identification of patients with moderate/severe dysplasia that would benefit from preventative treatments.
Couch G, Redman J, Wernisch L, Newton R, Malhotra, Dawsey S, Lao-Sirieix P, Fitzgerald RC. The discovery and validation of biomarkers for the diagnosis of esophageal squamous dysplasia and squamous cell carcinoma. Cancer Prev Res. 12 April 2016.
Further information on research carried out in the Fitzgerald group can be found here.
The 22nd Cambridge Science Festival was hailed as the biggest and best event ever by the organizers! The MRC CU was out in force at the Biomedical Campus on the last day of the Festival on March 20.
Recent years at the Cambridge Science Festival have seen a number of events being run on the Biomedical Campus (a move from a city centre location). While the MRC CU have previously staged talks/activities at the Clinical School, this year saw a change from this, with the CU working closely with colleagues from the Cambridge Cancer Centre (Department of Oncology and CRUK-CI) to present a series of talks and activities along the theme of 'Discover the world of cancer research'. The MRC CU ran six activities at the festival this year, which were based at the CRUK-CI.
A number of associated posters were made, explaining the work that we do at the Cancer Unit and providing some further information on the range of activities that we were running. A number of group leaders from the Unit also gave talks at the Festival. Prof Rebecca Fitzgerald gave a talk at Mill Lane on March 16 (Does a pill on a string hold the answer for earlier diagnosis of oesophageal cancer), while both Prof Ashok Venkitaraman (Making new medicines for old diseases) and Dr Shamith Samarajiwa (Battling cancer with data science) presented at the series of talks that were organised for the CRUK-CI Lecture Theatre on March 20. There was a great turn-out for the talks on the day, with many of the sessions at capacity.
There were a total of 18 volunteers from the Hutchison/MRC research centre at this year’s Festival. For many of us, this was our first time participating in the Festival, so it was a unique and exciting experience for all involved! A number of new activities were generated for this year's Festival, which proved to be very popular with the crowds! Volunteers from the Venkitaraman group developed a game based around the concept of designing a cancer medicine to attack cancer DNA. They designed a number of shapes, representing drug molecules, which were placed into a ‘lucky dip’ box. Visitors were then asked to select a molecule to see if it would be a good fit to target cancer DNA. The efficacy of the molecule was determined by the extent of DNA damage, which was represented by a series of cell-based images.
Members of the Shields and Vanharanta groups joined forces to develop and run a ‘Day in the life of a scientist’ activity. This involved a number of games revolving around commonly used laboratory techniques. These included an antibody generation and labelling game (labelling of tissue samples for microscopy) and a cell sorting activity (flow cytometry).
The two computational groups also joined forces (Hall group and Samarajiwa) to generate a pattern-searching activity, which demonstrated the role computers can play in detecting mutations in individual patients’ cancers. Paper codes were handed out to visitors to our activities (representing normal or mutant genes). Raspberry Pis (representing desktop sequencers) were then used to scan these codes to determine where each person’s code falls on a resulting graph (normal or mutant gene). This was used to demonstrate how computers can be used to determine genetic patterns of different cancer subtypes and how these patterns can be used to design personalised cancer therapies.
This activity was run alongside a ‘Bioinformatics Tombola’ activity, which was run by the Fitzgerald group. Each visitor to this activity was asked to select a coloured egg from the ‘tombola’ (representing a cancer cell), within which contained a short DNA sequence. Visitors were then asked to try and find this sequence within much larger sequence (a difficult task!). This was used to demonstrate the values of bioinformatics to find mutation patterns in the genomes of cancer patients. It also demonstrated how DNA sequencing technology can applied to characterise each patient’s cancer and to match patients to the right therapy for their type of cancer.
While many new activities were generated for this year’s Festival, some very popular and successful activities from previous festivals were brought out from storage and used once again! The invasion maze proved very popular with young and older children alike, who tried to make it through the maze in as quick a time as possible. It was a great way to demonstrate the importance of tumour cell invasion to early metastasis as well as the processes involved (with some help from our colourful poster!).
Many people in the Unit will also be familiar with ‘Norman’, a life-sized model of a human torso, which was developed over a number of years by the Fitzgerald group. In this model, the front is opened out to reveal the heart, lungs and gastrointestinal tract. This model was used to demonstrate some interesting biological processes to schools at the Schools Roadshow over many years. It has also proven very effective in demonstrating the how the Cytosponge™ (pill on a string) technology can be used to detect cancer at its earliest stages. Zarah Abdullahi presented this activity for the Fitzgerald group. She also brought along some slides of tissue representing healthy and diseased oesophageal tissue and used these to show visitors what these two tissue types look like under the microscope.
This is the first year that we have run our talks and activities from CRUK-CI and it has proven to be very successful! Many of the talks were full on the day and all of our volunteers reported great interest from the visitors that took part in their activities! Indeed, CRUK-CI reported that the crowd was significantly bigger than previous years. This success is largely due to the great enthusiasm and support from all of our wonderful volunteers! Thanks to all those that generously gave of their time to participate; giving talks, designing activities and posters, setting up the stands before the event and helping out on the day itself!
We think this conical flask on the left sums up the success of the event quite nicely. We asked our visitors if the event had improved their understanding of cancer research. We were delighted to see a majority of yes (blue discs) responses. Looking forward to the next round of public engagement events coming up later on this year!
We'll be at the Cambridge Science Festival on Sunday, 20 March, between 11am and 4pm. As in previous years, the Festival will be coming to the Cambridge Biomedical Campus. You will be able to find us at the CRUK-Cambridge Institute, along with our cancer research colleagues from the Cambridge Cancer Centre (Dept. of Oncology and CRUK-Cambridge Institute).
So, if you're interested in learning more about cancer research in Cambridge and trying your hand at some of the experiments we do in the lab, then do come along! As well as a feast of hands-on activities, researchers from the MRC Cancer Unit and CRUK-CI will give a number of exciting talks on the day itself. Further information can be found in the following links:
Prof Ashok Venkitaraman: Making new medicines for old diseases
Dr Shamith Samarajiwa: Battling cancer with data science
Dr Maike de la Roche: Harnessing our immune system to combat cancer
Dr Peter Maccallum: Big data from small sources
Full details and location maps can be found on the Cambridge Science Festival website.
- Dr. Carla Martins is a group leader at the MRC Cancer Unit. She is the senior author on a recently published paper in Nature. In collaboration with other researchers at the MRC Cancer Unit, her group have provided the first in-vivo evidence of metabolic rewiring in the malignant progression of lung cancer. This study also demonstrates that mutant Kras lung tumours are not a single disease, but a heterogeneous group of two classes of tumours, with distinct metabolic profiles, prognosis and therapeutic susceptibility. This is the subject of the following press release, which was recently issued by the Medical Research Council. -
24 February 2016
Scientists have discovered that lung cancers with extra copies of a cancer causing gene-defect ‘rewire’ their energy supply, helping them to survive and making them more likely to spread.
Researchers at the MRC Cancer Unit at the University of Cambridge studied lung cancers with mutations in their Kras genes, which are found in around 30 per cent of adenocarcinomas - the most common type of primary lung cancer. They found that the number of copies of Kras mutations had a profound impact on the disease, as those with extra copies undergo a change in their metabolism.
Lung cancer cells with extra copies of Kras mutations increase their uptake of glucose - the major energy source in the body - and show alterations in the way this sugar is processed. Changes in glucose metabolism are a well-known cancer trait but this study revealed that cells with extra copies of mutant Kras utilise glucose differently from those either with a single mutation or normal lungs.
This metabolic “rewiring” enables these cells to cope better with certain cellular stresses but also means that they have unique metabolic needs that can be exploited therapeutically. Since an increase in the number of copies of Kras mutations were associated with more aggressive tumour features, such as the ability to spread, the therapeutic implications of the study are particularly appealing.
Until now all lung cancers with faulty Kras genes have been seen as one form of the disease. Dr Carla Martins, the lead researcher based at the MRC Cancer Unit, said: “Our study shows that we have been wrong to view all lung cancers with Kras faults as one form of lung cancer. Recognising that they may comprise distinct disease groups can help us improve the way we diagnose and treat these cancers.
“This is something urgently needed for patients with this type of the disease as current treatments have limited success. We now need to build on this work by determining the prevalence of this metabolic rewiring in patients and find ways to exploit or prevent it.”
The study is published in Nature. PMID - doi:10.1038/nature16967
Further information on research carried out in the Martins group can be found here.
24 February 2016
Emerging evidence suggests that RNA processing pathways play a surprisingly intimate role in the cellular response to DNA damage. A recently published review by Prof Ashok Venkitaraman and Dr Vihandha Wickramasinghe in Molecular Cell (RNA Processing and Genome Instability: Cause and Consequence) provides an overview of recent insights into how RNA processing pathways contribute to DNA damage recognition, signalling and repair, and also selectively influence the expression of genome-stabilizing proteins and resolve deleterious DNA/RNA hybrids (R-loops) formed during transcription and RNA processing.
The significance of these pathways is highlighted by the growing evidence that faults in these regulatory connections may be associated with the genome instability implicated in many human diseases, including cancer. This knowledge (the mechanisms described in this review) will allow this research field to turn its attention to determine how disrupting these RNA processing pathways could promote carcinogenesis.
Further information on research carried out in the Venkitaraman group can be found here.
12 January 2016
Prof Rebecca Fitzgerald and her team have been successful in obtaining funding from Cancer Research UK for two new projects for 2016, which will support essential further research into efforts to improve the detection and diagnosis of oesophageal cancer and related conditions. These projects include the BEST3 trial and phase II of the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) collaboration.
Early detection of oesophageal cancer has been shown to improve patient outcome. However, most patients with heartburn (the primary risk factor) are not investigated. Hence most cases of oesophageal cancer present at an advanced stage. The BEST3 trial will assess whether the newly-developed CytospongeTM test for patients with reflux symptoms will be effective in increasing the detection of Barrett’s oesophagus. In Barrett's oesophagus the cells that line the lower gullet (oesophagus) are abnormal. The main cause is long-standing reflux of acid from the stomach (heartburn). People with Barrett's oesophagus have an increased risk of developing oesophageal cancer.
The CytospongeTM device will be trialed in GP practices using a cutting-edge cluster randomisation approach. Eighty GP surgeries will be randomised to either treat patients with reflux symptoms in the usual way or to offer all patients the opportunity to have a CytospongeTM test. Four thousand patients will be recruited to the trial, which will take 3 years to complete.
It is hoped that this research will establish whether the CytospongeTM test offers earlier detection and an alternative approach to invasive endoscopy. This will build on the previous multi-site BEST1 and 2 trials, providing the final step before this test could be introduced into main-stream practice in the UK. The project will be implemented in partnership with the Cancer Prevention Trials Unit at the Queen Mary University of London, and the Cambridge Institute of Public Health at the University of Cambridge.
Five years of funding has been secured by Prof Fitzgerald and her team for the second phase of the OCCAMS (Oesophageal Cancer Clinical and Molecular Stratification) collaboration. OCCAMS is a research study bringing together a network of clinical specialist centres treating patients with oesophageal cancer in the UK. Large-scale collection of clinical data and tissue is being used to help to identify clinical, demographic and molecular factors in the progression of oesophageal adenocarcinoma. Insights from the study will inform future trials of novel diagnosis and treatment strategies.
OCCAMS forms part of international sequencing efforts to generate a comprehensive catalogue of genomic abnormalities of cancer tumour types as part of the International Cancer Genome Consortium (ICGC). In collaboration with Simon Tavare’s group at the CRUK Cambridge Institute at the University of Cambridge, the project works to maximise the efforts of academic organisations and NHS trusts across the UK working in oesophageal cancer research.
- Dr. Christian Frezza is a group leader at the MRC Cancer Unit. He is the co-author (along with Dr. Sofia Costa from the MRC-CU) on a recently published paper in Nature Structural and Molecular Biology. In collaboration with researchers at the Wellcome Trust-CRUK Gurdon Institute, they have demonstrated and characterised a new form of DNA modification, which could open up the field of epigenetics. This is the subject of the following press release, which was recently issued by the University of Cambridge. -
21 December 2015
The world of epigenetics – where molecular ‘switches’ attached to DNA turn genes on and off – has just got bigger with the discovery by a team of scientists from the University of Cambridge of a new type of epigenetic modification.
Published today in the journal Nature Structural and Molecular Biology, the discovery suggests that many more DNA modifications than previously thought may exist in human, mouse and other vertebrates.
DNA is made up of four ‘bases’: molecules known as adenine, cytosine, guanine and thymine – the A, C, G and T letters. Strings of these letters form genes, which provide the code for essential proteins, and other regions of DNA, some of which can regulate these genes.
Epigenetics (epi - the Greek prefix meaning ‘on top of’) is the study of how genes are switched on or off. It is thought to be one explanation for how our environment and behaviour, such as our diet or smoking habit, can affect our DNA and how these changes may even be passed down to our children and grandchildren.
Epigenetics has so far focused mainly on studying proteins called histones that bind to DNA. Such histones can be modified, which can result in genes being switched on or of. In addition to histone modifications, genes are also known to be regulated by a form of epigenetic modification that directly affects one base of the DNA, namely the base C. More than 60 years ago, scientists discovered that C can be modified directly through a process known as methylation, whereby small molecules of carbon and hydrogen attach to this base and act like switches to turn genes on and off, or to ‘dim’ their activity. Around 75 million (one in ten) of the Cs in the human genome are methylated.
Now, researchers at the Wellcome Trust-Cancer Research UK Gurdon Institute and the Medical Research Council Cancer Unit at the University of Cambridge have identified and characterised a new form of direct modification – methylation of the base A – in several species, including frogs, mouse and humans.
Methylation of A appears to be far less common that C methylation, occurring on around 1,700 As in the genome, but is spread across the entire genome. However, it does not appear to occur on sections of our genes known as exons, which provide the code for proteins.
“These newly-discovered modifiers only seem to appear in low abundance across the genome, but that does not necessarily mean they are unimportant,” says Dr Magdalena Koziol from the Gurdon Institute. “At the moment, we don’t know exactly what they actually do, but it could be that even in small numbers they have a big impact on our DNA, gene regulation and ultimately human health.”
More than two years ago, Dr Koziol made the discovery while studying modifications of RNA. There are 66 known RNA modifications in the cells of complex organisms. Using an antibody that identifies a specific RNA modification, Dr Koziol looked to see if the analogous modification was also present on DNA, and discovered that this was indeed the case. Researchers at the MRC Cancer Unit then confirmed that this modification was to DNA, rather than from any RNA contaminating the sample.
“It’s possible that we struck lucky with this modifier,” says Dr Koziol, “but we believe it is more likely that there are many more modifications that directly regulate our DNA. This could open up the field of epigenetics.”
The research was funded by the Biotechnology and Biological Sciences Research Council, Human Frontier Science Program, Isaac Newton Trust, Wellcome Trust, Cancer Research UK and the Medical Research Council.
The text in this work is licensed under a Creative Commons Attribution 4.0 International License. - See more at: http://www.cam.ac.uk/research/news/epigenetic-discovery-suggests-dna-modifications-more-diverse-than-previously-thought#sthash.LxaSpyF1.dpuf.
Christmas Lights credit: Anthony Quintano.
The 2015 Hutchison/MRC Annual Retreat took place at the Granta Centre, Granta Park, in Great Abington in November. This retreat saw a slightly different approach being taken from previous years, with a dedicated poster session taking place at the Hutchison/MRC Research Centre on the afternoon before the retreat itself (an afternoon session on November 19th). Research centre staff and students alike were able to come along to this session, where they could enjoy some refreshements and view the posters presented in a relaxed setting. The session was very well attended and enjoyed by all.
Both the poster and oral competitions of the retreat were judged by members of the Hutchison/MRC Research Centre postgraduate and postdoctoral societies.
The poster competition was won by Dr. Emma Kerr for her poster entitled: ‘KRasG12D copy number defines metabolic reprogramming and therapeutic suscepatibilities’.
The runner-up prize was awarded to Callum Campbell for his poster entitled: ‘Understanding differential checkpoint responses to genetic lesions and their implications for oncogenesis: development and application of imaging tools’.
The main scientific sessions of the Annual Retreat took place the following day (November 20th), with presentations from both group leaders and postdoctoral researchers on a diverse range of ongoing research themes from around the building. Scientific sessions were chaired by members of the Hutchison/MRC Postdoc Society.
The award for best talk by a postdoctoral researcher was won by Dr. Hamza Chettouh for his talk entitled: ‘Early detection and risk stratification of patients with Barrett’s oesophagus using the CytospongeTM’. Dr. David Shorthouse took the runner-up prize for his computational biology talk entitled: ‘Osmotic regulation and cancer: Insights through the computational microscope’.
An additional non-scientific talk was given by PhD student, Maximilian Fries, who spoke about the Athena SWAN organisation (a UK-wide organisation aiming to increase gender equality and diversity in education and research) and how both staff and students can get involved with and benefit from this.
Congratulations to all the poster and oral prize-winners, with thanks also to the representatives of the Hutchison/MRC Research Centre postgraduate and postdoctoral societies who did such a great job in judging both the poster and oral competitions.
In maintenance (balanced) mode, the odds are balanced between production and shedding. In repair (expanding) mode, the odds of producing dividing cells are nine-times higher. CLICK TO ENLARGE.
Movies of cell growth explain skin graft success and may help understand cancer.
- Dr. Phil Jones is a joint faculty member of the MRC Cancer Unit along with the Sanger Institute. He is the senior author on a recently published Nature Cell Biology paper, which shows how skin cells can 'switch' between two growth modes to maintain or repair skin. The following extract is adapted from a press release issued by the Sanger Institute.-
How to maintain healthy skin and heal wounds is an intricate problem. Maintaining the skin requires exactly the right number of cells to divide to replace those shed from the skin surface. Too many cell divisions can lead to cancer, whereas too few will result in ulcers. Wound healing needs a short burst of cell production to fill the gap in the skin. Latest research shows that all dividing skin cells can flip between two probability game modes and so have the potential to both maintain and heal skin, challenging the view that only rare stem cells matter.
Understanding the rules of the games not only explains how skin maintains itself and heals wounds, but also shows how skin grafts work and suggests how changes to the rules could lead to cancer.
Watching high definition movies of human skin cells dividing in real time showed they play two types of dice game, for maintenance or wound repair. In the maintenance game, the odds are balanced between production and shedding, with a 50:50 chance of a daughter cell going on to divide or stopping division and migrating to the skin surface. These probabilities keep the skin in balance. However, cells next to a wound temporarily switch to the repair game, in which the odds of producing dividing cells are nine times higher, ensuring rapid healing.
“This research demonstrates that dividing human skin cells can switch their behaviour between these two modes of maintenance or repair, challenging the longstanding view that skin renewal and healing relies on a special population of stem cells,” says Dr Phil Jones, senior group leader at the Wellcome Trust Sanger Institute and MRC Cancer Unit, University of Cambridge.
To carry out the investigation of skin turnover, researchers took live imaging movies of more than 3,000 human skin cells dividing in culture. The images showed that single cells expanded exponentially in repair mode until they had produced multi-layered sheets of cells, after which the behaviour switched to maintenance mode. However, this is only half the story.
“By scratching sheets of cells in the balanced mode and observing cells next to the scrape, we saw that they changed into wound healing mode until the scratch was closed again,” says Dr Joanna Fowler, an author of the paper from the Sanger Institute. “The cells could switch backwards and forwards between the two states as required, proving that the behaviours were reversible.”
Skin loss due to burns or ulcers that won’t heal can be fatal and skin graft surgery is used to replace burnt or damaged skin. Sheets of skin can be grown from very small skin patches in the laboratory, and this can save the lives of patients with serious burns.
“As plastic surgeons, we have been growing sheets of skin from burns patients to save lives for decades. A single skin cell can create a patch of one centimetre diameter or more, and many of these together can make a whole sheet. However until now we couldn’t explain how this worked,” says Dr Amit Roshan, first author and Cambridge Cancer Centre Clinical Research Fellow at MRC Cancer Unit, Cambridge. “This research explains how skin cell cultures expand, and could lead to further improvements in wound healing in the clinic.”
The cells appeared to sense when their neighbours were missing, flipping from maintenance to wound healing behaviour: once they were surrounded by cells again, they flipped back. Inhibiting a cell signalling protein ROCK2 kinase prevented cells in expanding mode flipping back into balanced mode, indicating that cell signalling was required to make the switch. In further corroboration of the two mode games, the investigators found differences in gene expression between wound healing and balanced populations of cells.
“These findings have great implications for understanding cancer, where cells have too many dividing daughters. Mutations could change the rules of the game and load the dice in favour of dividing cells, leading to cancer.” Says Dr Phil Jones, “The knowledge that all dividing skin cells are the same but can switch their behaviour will help us understand how DNA changes associated with cancer alter cell behaviour.”
Human Keratinocytes have two interconvertible modes of Proliferation. Nature Cell Biology.
This work was supported by the Wellcome Trust, Cambridge Cancer Centre, Medical Research Council, the NC3Rs (National Centre for the Replacement, Refinement and Reduction of Animals in Research) and Cancer Research UK (Programme grant C609/A17257).
- Dr. Christian Frezza is the lead author from the MRC Cancer Unit on a recently published paper in Nature Materials, which describes the development of the first 3D tumour model to investigate how cancers adapt to low levels of oxygen. The following report has been adapted from a recent press release of the manuscript.
Scientists from the MRC Cancer Unit, working with researchers at the University of Toronto, have developed the first 3D model of a tumour to study how cancers can survive with low levels of oxygen. The model is a tissue-engineered platform, termed the Tissue Roll for Analysis of Cellular Environment and Response (TRACER).
It allows human cells to be cultured in a 3D-relevant environment (below left), in combination with the capacity to analyse variations in cell properties within the model. Such a tool will reveal more about the inner workings of cancers and help the development of new treatments.
This 3D model was created by coating a thin surface with cancer cells, then rolling this around a cylindrical core to create an environment (3D layered structure), where the innermost cells are deprived of oxygen. This establishes an oxygen gradient that mimics the same situation found within a tumour in the body. The researchers were then able to glimpse into the world of the tumour by rapidly unwinding the scaffold (below right).
Left: Photo of series of rollable tumours in a dish. Right: Thin strip containing cancer cells. [Please click image for video]
This revealed how the amount of oxygen varied within the tumour, and the implications this has on cell growth and treatment response.
The researchers were also able to reveal the metabolic responses cancer cells make to survive in a low oxygen environment. The lack of oxygen within a tumour is often down to the creation of new blood vessels lagging behind the cancers growth. To adapt to this, cells change their metabolic behaviour to cope, including their use of oxygen, to ensure continued growth and survival.
This response is controlled by a number of pathways so that some oxygen is able to permeate all the way through the tumour, ensuring that no cells die because they are completely starved of oxygen.
The 3D tumours also replicated a cancer’s response to treatment – levels of the common chemotherapy drug doxorubicin plateaued deeper into the tumour. The response to radiotherapy was also similar to that seen in humans where cells with low oxygen were less likely to die.
Dr Christian Frezza, the lead researcher from the MRC Cancer Unit, said: “Cancers grow rapidly, and to support this growth, cells need to be able adapt in an environment where the supply of oxygen can’t keep up. While this phenomenon has been known for some time, gaining an experimental insight to the metabolic processes that the cells use to survive has proved a challenge.”
“Our new model allows us to look at cellular metabolism in 3D to investigate how a tumour response to low oxygen is tightly controlled, and how cells are unable to adapt and survive without this control. This knowledge could lead to the development of new treatments that target these oxygen deprived cancer cells, which can be the hardest to target and destroy.”
The study is published in Nature Materials.
TedXUofT talk on paper by AP McGuigan
- Dr. Phil Jones is a joint faculty member of the MRC Cancer Unit along with the Sanger Institute. He is an author on a recently published Science paper, which demonstrates that an unexpectedly high number of cancer-associated mutations occur in normal skin. The findings of this study were the subject of a recent press release issued by the Sanger Institute.-
This study illuminates the first steps cells take towards becoming a cancer and demonstrates the value of analysing normal tissue to learn more about the origins of the disease.
The study revealed that each cell in normal facial skin carries many thousands of mutations, mainly caused by exposure to sunlight. Around one in four skin cells in samples from people without cancer were found to carry at least one cancer-associated mutation. Ultra-deep genetic sequencing was performed on 234 biopsies taken from four patients revealing 3,760 mutations, with more than 100 cancer-associated mutations per square centimetre of skin. Cells with these mutations formed clusters of cells, known as clones, that had grown to be around twice the size of normal clones, but none of them had become cancerous.
Dr Peter Campbell, a corresponding author from the Wellcome Trust Sanger Institute explains:- “With this technology, we can now peer into the first steps a cell takes to become cancerous. These first cancer-associated mutations give cells a boost compared to their normal neighbours. They have a burst of growth that increases the pool of cells waiting for the next mutation to push them even further. We can even see some cells in normal skin that have taken two or three such steps towards cancer. How many of these steps are needed to become fully cancerous? Maybe five, maybe 10, we don’t know yet.”
The mutations observed showed the patterns associated with the most common and treatable form of skin cancer linked to sun exposure, known as cutaneous squamous cell carcinoma, rather than melanoma, a rarer and sometimes fatal form of skin cancer.
Dr Iñigo Martincorena from the Sanger Institute is the lead author on this study. She says:-
“The burden of mutations observed is high but almost certainly none of these clones would have developed into skin cancer. Because skin cancers are so common in the population, it makes sense that individuals would carry a large number of mutations. What we are seeing here are the hidden depths of the iceberg, not just the relatively small number that break through the surface waters to become cancer.”
Skin samples used in this study were taken from four people aged between 55 and 73 who were undergoing routine surgery to remove excess eyelid skin that was obscuring vision. The mutations had accumulated over each individual’s lifetime as the eyelids were exposed to sunshine. The researchers estimate that each sun-exposed skin cell accumulated on average a new mutation in its genome for nearly every day of life.
Dr Phil Jones, a corresponding author from the Sanger Institute and the MRC Cancer Unit at the University of Cambridge notes:-
“These kinds of mutations accumulate over time – whenever our skin is exposed to sunlight, we are at risk of adding to them. Throughout our lives we need to protect our skin by using sun-block lotions, staying away from midday sun and covering exposed skin wherever possible. These precautions are important at any stage of life but particularly in children, who are busy growing new skin, and older people, who have already built up an array of mutations.”
Recent studies analysing blood samples from people who do not have cancer had revealed a lower burden of mutations, with only a small percentage of individuals carrying a cancer-causing mutation in their blood cells. Owing to sun exposure, skin is much more heavily mutated, with thousands of cancer-associated mutations expected in any adult’s skin.
The research was primarily supported by the Wellcome Trust, the Medical Research Council, Cancer Research UK and EMBO.
-Adapted from a press release issued by the Wellcome Trust Sanger Institute.
See more at: https://www.youtube.com/watch?v=s0XlI7b87qA&feature=youtu.be
The text in this work is licensed under a Creative Commons Attribution 4.0 International License. -http://creativecommons.org/licenses/by/4.0/
- Dr. Rebecca Fitzgeralds Group have recently published a paper in Nature Genetics wherein they describe the heterogeneity of the clonal architecture in Barrett’s oesophagus and oesophageal adenocarcinoma. Their findings strengthen support for the molecular Cytosponge technique, which overcomes sampling bias and has the capacity to reflect the entire clonal architecture. A press release based on this work and the Cytosponge technique was recently published in the Telegraph and shown below.-
Cambridge University has developed a quick way of testing for gullet cancer using a tiny sponge on a string.
The pill on a string which dissolves into a sponge
By Sarah Knapton, Science Editor
4:17PM BST 20 Jul 2015
A ‘pill on a string’ has been developed by the University of Cambridge to detect the early signs of gullet cancer without the need for a biopsy. The pill is swallowed and when the outer case dissolves it reveals a sponge which can then be pulled up the throat lining, collecting cells. Researchers say the tiny sponge is more effective at picking up cancer because it takes a swab of the whole throat and not just a small area that a biopsy would examine. Oesophageal cancer is often preceded by Barrett’s oesophagus, a condition in which cells within the lining of the oesophagus begin to change shape and can grow abnormally.
When the pill dissolves it turns into a sponge.
Between one and five people in every 100 with Barrett's oesophagus go on to develop oesophageal cancer in their life-time, a form of cancer that can be difficult to treat, particularly if not caught early enough. The new test can pick up the earlier condition which means treatment can start sooner. “The trouble with Barrett’s oesophagus is that it looks bland and might span over 10cm,” said Professor Rebecca Fitzgerald, at the Medical Research Council Cancer Research Unit at the University of Cambridge. “There is a great deal of variation amongst cells. Some might carry an important mutation, but many will not. If you’re taking a biopsy, this relies on your hitting the right spot. “Using the sponge appears to remove some of this game of chance.”
The team has taken samples from 73 cancer patients over three years so that they know exactly which mutations indicate that the disease is present. They found patterns of changes where one letter of DNA had been switched for another to provide a ‘fingerprint’ of cancer.
The researchers also discovered that there appeared to be a tipping point, where a patient would go from having lots of individual mutations, but no cancer, to a situation where large pieces of genetic information were being transferred between chromosomes. Co-author Dr Caryn Ross-Innes adds: “We know very little about how you go from pre-cancer to cancer – and this is particularly the case in oesophageal cancer. “Barrett’s oesophagus and the cancer share many mutations, but we are now a step closer to understanding which are the important mutations that tip the condition over into a potentially deadly form of cancer.” The research was funded by the Medical Research Council and Cancer Research UK.
Dr. Ben Hall has recently had his work published in Biophysical Journal, entitled: ‘Emergent Stem Cell Homeostasis in the C. elegans Germline Is Revealed by Hybrid Modeling’. Some of this work was selected as a covering image for the journal (below). In the following report, Dr. Hall discusses the rendering of this colour image and his groups innovative work with computational models of Cancer Biology.
Stem cells are fundamental building blocks for organ growth. They are cells that have not committed to doing a specific job and, therefore, can be directed by different signals to perform a wide range of tasks. The cover image shows the shapes of stem cells while they undergo the process of organ growth, in a computational model. The cells themselves are packed tightly, and so to reduce the amount of unused space in the organ they form a hexagonal arrangement. This isn’t unique to cells; if you pack oranges or balls on a shelf tightly you can see the same kind of packing. The type of packing reflects both the shape of the cells, and the amount of crowding in their environment.
Our simulations don’t generate these images automatically. When we want to analyse this type of system we take the raw data, typically in a text file, and use a specialized tool to view it as a 3D object. We did this using the tool VMD (http://www.ks.uiuc.edu/Research/vmd/) and rendering the cells as spheres. This is a very powerful way to show how the cells move and grow and is important for many types of analysis.
For this image we wanted to generate a different kind of visualization. We wanted an image that showed the cell packing unambiguously and more closely resembled the experimental microscopy data. To do this we performed a mathematical analysis—a Voronoi decomposition—to calculate the edges of the cells. For each cell we then rendered these faces as colored blue glass and drew in a small green sphere to show the center of the cell. This clearly shows how cells in the niche pack hexagonally, and the resulting image resembles the microscopy images much more closely. This makes direct comparison much simpler and can be used to validate the simulations.
Both the cover image and our article show what can be done using detailed computational models to understand organ growth. Although the work is focused on one specific system—the germline from the nematode C. elegans—both the model and the approach may have significant impacts beyond this system. The organ structure, a stem cell niche, is found commonly in many different systems, and just as tumors may grow in the C. elegans germline, mutations may cause human stem cell niches to develop into cancers. Similarly, our group at the MRC Cancer Unit, University of Cambridge, is looking to use the same methods and tools to model different pre-cancer and cancer systems. This includes studying detailed models of individual components and large biochemical networks in cells. The Fisher group at Microsoft Research and the Department of Biochemistry, Cambridge University, is using the same computational methods to model the molecular mechanisms underlying cancer (e.g., leukaemia, glioblastoma) as well as blood development.
For information on our research, visit the group’s website and blog http://drhallba.wordpress.com. For information on the Fisher group, view http://research.microsoft.com/en-us/people/jfisher/ and recent press release related to their work on blood development http://research.microsoft.com/en-us/news/features/leukemia-drugs-computer-model.aspx.
– Benjamin A. Hall, Nir Piterman, Alex Hajnal, Jasmin Fisher
Researchers have discovered the atomic structure of a protein which controls how cells make decisions, and which may cause skin disease and predispose cells to cancer, challenging received wisdom about how it works. The new results suggest that tiny movements, on the scale of a millionth of a millimetre, effectively switch the protein on and off, driving changes in cell behaviour.
Through a large interdisciplinary collaboration funded by the Medical Research Council, Cancer Research UK, the Wellcome Trust and the Royal Society, researchers at Birkbeck, UCL and Cambridge worked together to use advanced techniques from biology, physics, and computational science to show what the protein, IKK-gamma, looks like and how it moves. From this, they proposed how it initiates different cellular behaviours.
IKK-gamma is long and flexible, and as such standard approaches such as X-ray crystallography could only show the structure of small fragments. To overcome this, the team used a magnetic resonance technique whereby molecular sized magnets were attached to the protein as labels. When placed into a strong magnetic field, pairs and quartets of these labels respond to microwaves, and allow the distances between them to be measured. By putting sets of labels in different locations in the protein the distances between different parts of the protein could be calculated. The results were then used to choose between different proposed structures until only one compatible structure remained.
Professor Chris Kay, from UCL, commented that “the study shows how powerful interdisciplinary work can be. None of the approaches on their own could give us this much insight into how IKK-gamma works.”
Dr Ben Hall, from the MRC-Cancer Unit at University of Cambridge added “Through bringing together state of the art modelling approaches with experiment we’ve been able to show how small changes may tweak the structure of the protein, which in turn leads to whole-cell and even tissue behaviour.”
This work gives an unprecedented insight into how a single protein may control large numbers of signalling networks. These findings also suggest how proteins from other biological systems with similar structures integrate information in the cell.
Commenting on the findings, which were published this month in the Journal of Biological Chemistry, Dr. Ben Hall said: “This is the most complete view of IKKG ever achieved. The combination of both the level of detail seen and the completeness of the data are the first step to thinking about how understand how IKKG goes wrong in different diseases, and how treatments may be designed in future to correct these mistakes.”
Bagnéris C, Rogala KB, Baratchian M, Zamfir V, Kunze MB, Dagles S, Pirker KF, Collins MK, Hall BA, Barrett TE, Kay CW.Probing the Solution Structure of IκB Kinase (IKK) Subunit γ and its Interaction with Kaposi's Sarcoma Associated Herpes Virus Flice Interacting Protein and IKK Subunit β by EPR Spectroscopy..J Biol Chem. 2015 May 14. pii: jbc.M114.622928. [Epub ahead of print].
Video: Dr Ben Hall discusses his research. Ben_H_00015 (4)
Our building, the Hutchison/MRC Research Centre, was Highly Commended at this week's annual EAUC Green Gown Awards. Now in their 10th year, the Green Gown Awards recognise the exceptional sustainability initiatives being undertaken by universities and colleges across the UK. The Research Centre was a finalist in the Technical Innovation for Sustainability category, based on its use of demand ventiliation control (a first in the UK). This system, along with an improved environmental culture amongst all occupants of the building, has resulted in a significant reduction in gas and electricity consumption, resulting in both financial savings and reduced carbon emissions. We hope that this award facilitates the sharing of best practice with other research institutions.
For more information about the awards visit the EAUC Green Gown website.
For more information about green activities within the MRC Cancer Unit and Hutchison/MRC Research Centre visit our energy and environment pages.
Congratulations to our programme leader, Professor Rebecca Fitzgerald, who has been awarded this year's UEG Research Prize for her pioneering work on early detection methods for oesophageal cancer. The annual prize, worth €100,000, is awarded each year for excellence in basic science, translational, or clinical research, and researchers must also be able to demonstrate that their previous work has had an impact in its field and is recognised internationally. Rebecca's work was particularly noted for its "practical and innovative approach to important clinical problems, which maximizes the potential for successful application".
The Prize will will support a research project entitled: Combination of quantifiable genomic assays with a patient friendly non-endoscopic cell retrieval device called Cytosponge™ for management of patients with Barrett’s oesophagus. The aim of the project is to bring the biomarker research undertaken by the Fitzgerald group to routine clinical practice.
For more information visit the UEG website.