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A Three-Dimensional Tumour Model Replicates Oxygen Starvation in Cancers

last modified Dec 03, 2015 10:31 AM

November 2015

- 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]

Photo of series of rollable tumours in a dish. Thin strip containing cancer cells. [Please click 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.

3dtumourmodel3
Imaging of stacked layers to measure oxygen levels through engineered tumour.
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. 

3dtumourmodel4
Cellular organization in the engineered tumour.


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

 


Cancer Associated DNA Changes Identified in Almost a Quarter of Normal Skin Cells

last modified Dec 08, 2015 04:54 PM

August 2015


- 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/


Pill on a String can Detect Cancer Without Need for Biopsy

last modified Dec 03, 2015 10:24 AM

July 2015

- 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.

newsletter

 

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.

 

newsletter

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.

 

Professor Rebecca Fitzgerald discusses the Cytosponge technology (video).

 

Other key articles of this work were published by the Daily Mail NewsweekGizmagCambridge News , and WebMD .


Stimulating Cell Packing to Understand Human Growth

last modified Dec 01, 2015 06:10 PM

July 2015

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.

newsletterOur 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


Cells behaving badly: researchers discover switch that may trigger cancer

last modified Dec 09, 2015 11:00 AM

June 2015

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].

 

Ikk Gamma
Figure: The solution structure of IKK-gamma (found using molecular modeling and EPR)

                                                               

 

                                                                       

 

 

 

 

 

                                                                         Video: Dr Ben Hall discusses his research. Ben_H_00015 (4)

 

Hutchison/MRC Research Centre Highly Commended at EAUC Green Gown Awards

last modified Dec 01, 2015 06:11 PM

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.


MRC Cancer Unit Programme Leader Wins United European Gastroenterology (UEG) Research Prize

last modified Dec 01, 2015 06:12 PM



rcf 2014smCongratulations 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.