New hydrogel technology has promise in breast cancer modelling

In science, a model is used as a representation of something in the real world, so that ideas and concepts may be tested out. Models have a variety uses, but in cancer biology they are often popular as they can help to mimic the complex environment seen in human   disease. Models are used to explore the effects of new drugs, understand genetic or cellular pathways on tumour development or predict the potential response of a patients cancer.

It’s in a researcher’s best interest to create a model that is as faithful to the real world as possible, so that the outcomes are accurate and can translate successfully into humans. However, the go-to models to recapitulate human cells in a lab use, a protein matrix extracted from mouse tumours, which is used to resemble the extracellular environment found human tumours. But the extent to which mouse matrix can be used is limited by its fixed extracellular matrix components, which are often not representative of the human tissue, and the inability to add or remove the individual extracellular components to explore the influence these on tumour growth.

Dr Gillian Farnie, Nuffield Department of Orthopaedics, Rheumatology and Musculorskeletal Sciences, has focused her work on developing new models that allow human breast cancer cells to be grown and researched, whilst overcoming these limitations.

A recent publication in Matrix Biology, funded by the NC3Rs, outlines a new peptide hydrogel developed by the Farnie group in collaboration with Prof Merry (University of Nottingham).  This new peptide hydrogel offers the added benefit of being customisable, by incorporating or removing specific extracellular matrix components that researchers want to test, to better understand their influence on cancer cells. It therefore allows full control over the biochemical and physical properties of the model, providing researchers with the opportunity to more accurately adapt the model to the real-life environment of human breast tumour.

The new technology’s applications are incredibly widespread and promising. For example, certain extracellular matrix proteins, when found in high quantities in a tumour, can often be associated with a poorer prognosis for a patient. Researchers may want to understand if this is a simple correlation, or if the proteins are assisting the cancer in some way, such as promoting treatment resistance. The ability to remove these proteins from a cancer model and test the response, whilst remaining faithful and accurate to human cells, is incredibly useful and can allow us to discover therapeutic targets.

Dr Gillian Farnie is currently working with the breast cancer research community to apply this new technology in multiple breast tumour research projects. The hydrogel’s applications are not limited to just matrix biology, but also in investigating areas such as the biological significance of blood vessel supply to tumours or even other cancer types outside the breast.

This new hydrogel provides an opportunity to better understand the individual influences of the extracellular matrix, mechanical properties and cell-cell interactions on breast cancer and other disease. It is an open and reproducible model that Dr Farnie is currently publishing a detailed methodology in JOVE, so that more cancer researchers can have access to the new technology.

About this research

Dr Gillian Farnie is based in the Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences.  Her research focuses on the development of patient derived pre-clinical breast cancer models that are used to examine mechanisms of inherent and induced therapy resistance, interrogating both intra-tumour heterogeneity (cancer stem cells) and the tumour microenvironment (ECM, Stroma, Immune cells).

Using big data in breast cancer research

Breast cancer is the most common type of cancer found in the UK population, with 1 in 8 women diagnosed during their lifetime. As a prevalent cancer, it’s important to understand more about the potential causes and relative risks that individuals from different demographics might have.

The Cancer Epidemiology Unit (CEU) at the Nuffield Department of Population Health specialises in large-scale studies into the lifestyle and genetic risk factors of cancers such as breast cancer. In doing so, these studies can provide evidence to inform public health policies and answer outstanding questions about how cancers may arise.

The cause of breast cancer has long been researched and over the last two decades, findings from the Unit’s large prospective studies and international collaborations have helped clarify the role of many risk factors for the disease, including use of menopausal hormones and oral contraceptives, as well as factors relating to childbearing. Within the last year, an updated review of the worldwide evidence carried out in CEU showed that menopausal hormone usage increases the long term risk of breast cancer by almost twice as much as was previously thought, findings which influenced public health guidance. Other recent work found evidence to suggest that high fruit and fibre intake and physical activity may be associated with lower risks of breast cancer.

The CEU work with big data, such as its Million Women Study which contains data from 1.3 million UK women, collected since it began  in 1996. The study includes 1 in 4 of all UK women born between 1935 and 1950 and remains the largest data set of its kind. The study, which aims to resurvey women every 3-5 years, continues to collect information on new potential risk factors such as working night-shifts (which in this case was shown to have no influence on breast cancer incidence).

Enhancing the quality and quantity of the Million Women Study dataset is high on the CEU’s agenda. One area of research where the study hopes to be able to contribute substantially over the next few years is in risk stratification for breast cancer. Prediction models which can be used to assess an individual’s breast cancer risk are key for planning risk-based screening approaches that are tailored to an individual, so refining their accuracy is important to ensure that interventions can be targeted appropriately. However, while existing risk prediction models look promising they need further improvement in their ability to identify those women who are most likely to get breast cancer before they can be applied at a population level. In particular, models should ideally incorporate the whole spectrum of breast cancer risk factors including genetic variation and radiological imaging data.

This will be the next stage for the Million Women Study, as Prof Gill Reeves, Head of the CEU, hopes to integrate new datasets into the study. This includes digital screening images from mammograms, and other clinical information, which could be used in combination with existing information held on participants, to allow the CEU to develop more accurate risk prediction models from the Million Women’s Study.

Prof Gill Reeves, Head of the CEU, says:

“Enriching the quality of datasets such as the Million Women Study will allow us to continue to provide reliable evidence regarding the effects of behavioural and biological factors on breast cancer risk, and help identify women who are at particularly high risk of the disease. In doing so, we can better inform public health advice, and clinical practice.”

To read more about the CEU’s work on breast cancer go to the  CEU website.

About the CEU

The CEU runs the Million Women’s Study (MWS) and EPIC-Oxford (two large cohort studies). Recent grant funding from CRUK has allowed for further enhancement of the MWS so that new clinical data and other potential risk factors for cancer may be integrated.

Prof Gill Reeves, Head of the CEU, is a Professor of Statistical Epidemiology. Her main research interests are the roles of hormonal and other risk factors in the development of female cancers.  She is particularly interested in risk factors and patterns of survival for molecular subtypes of breast cancer.

 

Funding boost for OxPLoreD early detection study

OxPLoreD is an observational cohort study sponsored by Johnson and Johnson that will recruit 1650 patients from across the UK with pre-cancerous lymphoproliferative disorders. These conditions include monoclonal B-cell lymphocytosis and monoclonal gammopathy of unknown significance that put individuals at higher risk of developing the blood cancers chronic lymphocytic leukaemia and multiple myeloma respectively.

The aim of the study is to look for new ways to find and treat blood cancer sooner by identifying clinical, genomic and immunological predictive markers of progression from these pre-cancerous conditions to malignant disease. The study will also explore the possibility of a future early intervention trial for the subgroup of patients at highest risk of progression.

OxPLoreD is one of the seven clinical trials that have received an £8m funding boost from UK Research and Innovation (UKRI) and will work in partnership with Genomics England. The funding will speed up the adoption of whole genome sequencing in the study of cancer. Genetic analysis is a critical tool that can allow clinicians to select the most appropriate treatments for each patient. In the OxPLoreD study, genetic analysis might be able to identify individuals at highest risk of disease progression that would benefit from earlier treatment. In the longer term this may also enable the identification of those people who would benefit from certain types of treatment.

Alison Cave, UKRI challenge director says:

“Research tells us that one-in-two people in the UK population will get cancer. That stark statistic shows just how important it is for us to seek new treatments. The use of genetic analysis opens new possibilities in our drive to beat cancer. The projects for which we have announced funding today are exciting pointers to future diagnosis and precision treatments”

The funding has been delivered through UKRI’s Industrial Strategy Challenge Fund’s £210m data to early diagnosis and precision medicine (DEDPM) programme. The challenge aims to combine research data and evidence from the NHS to create new and improved ways of identifying disease and treatment pathways.

Prof. Sir Mark Caulfield, Chief Scientist at Genomics England says:

“The 100,000 Genomes Project, Genomics England has analysed the genomes of over 17,000 cancer participants and this suggests that up to half have revealed mutations of potential clinical significance. The DEDPM programme is a major opportunity to expand the application of whole genome sequencing into clinical trials involving cancer where support from the ISCF is likely to deliver significant clinical benefit”

For more information about the other trials funded by this scheme, see the UK Research and Innovation announcement.

A new FRONTIER for breast cancer

Latest news from FRONTIER, the trial investigating the potential of the radiotracer Fluciclovine in the subtyping and staging of breast cancers

Oxfordshire-based SCAN pathway wins BMJ award

Every year, the British Medical Journal (BMJ) runs a competition to find the cancer care team that has developed new approaches to improve cancer diagnosis and treatment. This year, six teams were shortlisted from across the UK and on the 7th October it was announced that the Oxfordshire-based SCAN pathway had won this year’s award.

The Suspected CANcer (SCAN) pathway is designed to accelerate cancer diagnosis in patients with non-specific cancer symptoms. The UK performs worse than many other developed nations in terms of cancer survival and this is in part due to the fact that 21% of cancers are diagnosed after emergency presentation, when they are often at a later stage and more difficult to treat successfully.

In an effort to improve these statistics, urgent referral pathways for suspected cancer have been developed for symptoms specific to one cancer site. However, one in five people diagnosed with cancer only ever report non-specific symptoms of cancer, such as unexplained weight loss, fatigue, nausea, or abdominal pain. These people often experience delays due to being referred sequentially to multiple different tumour site-specific clinics before receiving a diagnosis. The SCAN team identified this unmet need and designed and implemented a new diagnostic pathway that straddles primary and secondary care for patients with non-specific but concerning cancer symptoms.

Patients are referred by their GP to the pathway based in the Churchill Hospital, Oxford, where they are investigated with a whole body computed tomography (CT) scan and undergo blood and stool testing. The outcome of these tests directs the patient to the most appropriate clinical expertise to reach a diagnosis as quickly as possible.

Since its implementation across Oxfordshire in November 2017, the SCAN pathway has seen 2148 patients and diagnosed 201 incidences of cancer, most commonly lung, bowel, pancreas, lymphoma and breast. In addition to cancer diagnoses, the SCAN pathway has diagnosed a large number of serious non-cancer conditions, including tuberculosis, endocrine diseases and inflammatory bowel disease.

“One of the unique features of the SCAN Pathway is that for the remaining patients who do not receive a cancer diagnosis, we offer GPs the option for these patients to have a general medical review in a further attempt to reduce onward referrals.”

  • Julie-Ann Moreland, Macmillan Project Manager and SCAN Navigator, Oxford Radiology Research Unit

Since the SCAN pathway’s inception, the number of GP surgery visits and secondary care referrals prior to receiving a cancer diagnosis decreased by approximately 4-fold, saving a large number of NHS appointments, and the time to diagnosis has reduced. Patients have also responded positively about the service in patient satisfaction questionnaires.

“Prior to the SCAN pathway, patients with non-specific symptoms were having to go to the GP on average 7.8 times and be referred to numerous secondary care clinics before receiving a diagnosis. The SCAN pathway decreases the time to diagnosis and allows patients to start receiving important treatments earlier. This will not only improve patient outcomes but will also reduce the anxiety experienced by patients while waiting for a diagnosis”

 

 “I am delighted that the SCAN team have received this recognition from the BMJ. The judges made a special mention of the holistic care that the clinical team works so hard to provide. Given its success, we are introducing the pathway across the Thames Valley Cancer Alliance and other regions. We are gathering data as we go so we can learn how to improve the service for patients.”

  • Dr Brian Nicholson, Academic GP Lead, Nuffield Department of Primary Care Health Sciences

 

“The development and implementation of the SCAN Pathway has been the result of hard work and collaborative teamwork with passionate people who have strived to develop a service focusing on improving the experience for patients.

“To even be short listed for this award is an incredible achievement and so to win it has been a fantastic and unexpected surprise. We are all very proud of this new pathway and this is a brilliant way to receive recognition and celebrate that.”

  • Zoe Kaveney, Cancer Programme Manager at Oxfordshire Clinical Commissioning Group

 

The SCAN pathway was supported by the Accelerate, Coordinate, Evaluate (ACE) programme funded by NHS England, Cancer Research UK and Macmillan, and the Oxfordshire Clinical Commissioning Group.

Understanding breast cancer management in women of different ethnicities

Dr Toral Gathani investigates the associations between ethnicity and the surgical management of breast cancer, to help understand any observed differences in patterns of treatment in women of different ethnic groups.

Prof. Ellie Barnes comments on the 2020 Nobel Prize for Medicine

Prof Ellie Barnes comments on the recent Nobel Prize in Medicine, awarded to Harvey J. Alter, Michael Houghton and Charles M. Rice for their discovery of the Hepatitis C virus, a major global health problem and a cause of cancer

In 1989, Harvey J. Alter, Michael Houghton and Charles M. Rice used what at the time were state-of-the-art technologies available to identify the virus that causes Hepatitis C infection. This ground-breaking discovery allowed for the development of blood tests to diagnose the Hepatitis C Virus (HCV) and saved millions of lives over the last 40 years.

Testing for HCV has enabled the discovery of chronic infections that results from the Hepatitis C virus. Currently 71 million people are living with HCV, as there is no vaccine to prevent infection. HCV remains a silent disease that is often only diagnosed until symptoms of late-stage liver disease develop. In many cases, it goes undetected until severe complications occur, the most serious of which is hepatocellular carcinoma (HCC). By this point, existing treatments are often less effective at clearing the infection.

Hepatocellular carcinoma is the most common type of primary liver cancer, which is common in those who have had liver scarring due to Hepatitis B and C infections. 400,000 people globally die each year from HCV, with hepatocellular carcinoma continually on the rise. As a result, viral hepatitis is still one of the most serious global pandemics at large. Due to the lack of an effective HCV vaccine and early detection methods for the diagnosis of hepatocellular carcinoma, it is crucial to develop techniques that can aid its early detection and thereby increase the survival rate of cancer patients.

Prof Ellie Barnes at the Nuffield Department of Medicine, leads the DeLIVER study for the early detection of hepatocellular carcinoma that builds on the seminal work as recognised with this year’s Nobel Prize. On the topic of this year’s Nobel Prize winners, she says:

“Now, we need to repeat what those Nobel Prize winners did in 1989 for liver cancer. Like them, we can use today’s new advances in imaging and molecular technology to identify hepatocellular carcinoma at an earlier stage when it is still curable.

“The techniques to do this have advanced remarkably over the last 40 years and it should be possible, with carefully designed patient cohorts and inter-disciplinary effective co-working. By building on the work of Alter, Houghton and Rice, we can do it.”

The risk of liver cancer is increased by viral hepatitis infections, alcohol and obesity, causing the immune system to attack the liver leading to scarring and liver cirrhosis. Monitoring of people with these conditions can reduce mortality but current diagnostic tests for hepatocellular carcinoma fail to detect cancer in many cases.

The DeLIVER team is building on the work of Nobel Prize winners through the use of state-of-the-art multiparametric imaging, viral genetics, and liquid biopsy technologies (such as TAPS) to identify the early indicators of liver cancer by studying people at risk, such as those with Hepatitis C, over several years.

About DeLIVER

DeLIVER is a CRUK-funded programme led by Professor Ellie Barnes that aims to better understand the pre-cancerous changes in the liver and use this knowledge to inform new technologies for early HCC detection. The study will receive patient input from the British Liver Trust and the Hepatitis C Trust.

You can read more about it on the OxCODE website here.

How chemotherapy impacts the body

Current standard cancer treatments, such as chemotherapy and radiotherapy, can have lasting effects on the body. Chemotherapy for example is associated with many side effects, such as nausea and anaemia, due to the impact of the toxins on healthy tissue as well as the tumour.

Neoadjuvant therapy, whereby therapies are administered before the main treatment, to help reduce the size of a tumor or kill cancer cells that have spread, has previously been suggested to contribute to changes in the composition of a patient’s body. This includes reduction in muscle mass (or ‘sarcopenia’) which is a natural result of aging, but in those with cancer it can lead to some post-operative complications and other diseases further down the line.

A new study from Mr Nick Maynard, Oxford University Hospitals Trust, has assessed the changes in muscle mass in gastro-oesophageal cancer patients, to better understand the long-lasting impact therapies have on the body and if it can be used to predict the risk of post-op complications. From a sample of 199 patients, they observed a decrease in skeletal mass in all individuals, with 91 participants losing more than 5% of their original skeletal mass. Those with a high rate of muscle mass depletion were generally male and significantly older, i.e. over the age of 67 years old.

50% of patients in the study experienced post-operative complications, such as pneumonia, with 13% having severe complications. However, Nick and the team observed that this was not related to the patient’s loss of skeletal mass.

Fortunately, this means that patients undergoing surgery for oesophageal cancer with large reductions in muscle mass are not necessarily at an increased risk of post-operative complications. Whilst these results do not produce any new method for predicting post-op complications, as sarcopenia did not determine the frequency of post-op complications in the sampled patients, they provide a deeper understanding of how neoadjuvant therapies can impact the body. This is important as post-operative loss of muscle mass has been previously associated with a lower survival rate for oesophageal cancer patients, so this will help to inform clinicians which patients may need to be more closely monitored.

New AI technology to help research into cancer metastasis

Cell migration is the process of cells moving around the body, such as immune cells moving through the body’s tissues to fight off disease, or the cells that move to fill the gap where a tissue has been injured. Whilst cell migration is an important process for regeneration and growth, it is also the process that allows cancer cells to invade and spread across the body.

Therefore understanding the factors that regulate and instruct cells to move is an important part of understanding how we can prevent the metastasis of many cancers. One method of doing this is through scratch assays, which as the title suggests, involves inflicting a wound or ‘scratch’ on cells grown in a petri-dish and analysing how the surrounding cells react and migrate to ‘heal’ the scratch under a microscope.

Although cell migration is intensively studied, we still do not have efficient therapies to target it in the context of cancer metastasis. Observing cancer cell behaviour to artificial wounding and how this can be altered in response to pharmacological drug treatment or gene editing is important to fully understand the factors that drive this process in tumours and provide insights on the processes that drive such behaviours. Whilst current microscopic analysis methods of wound healing data are hindered by the limited image resolution in these assays. Therefore, there is a need to develop new methods that overcome current challenges and help to answer these questions.

Dr Heba Sailem a Research Fellow from the Department of Engineering, has led a study to develop a new deep learning technology known as DeepScratch. DeepScratch can detect cells from heterogenous image data with a limited resolution, allowing researchers to better characterise changes in tissue arrangement in response to wounding and how this affect cell migration.

Tests using the technology have found that DeepScratch can accurately detect cells in both membrane and nuclei images under different treatment conditions that affected cell shape or adhesion, with over 95% accuracy. This out-performs traditional analysis methods, and can also be used when the scratch assays in question are applied to genetically mutated cells or under the influence of pharmaceutical drugs – which makes this technology applicable to cancer cell research too.

Dr Heba Sailem says;

“Scratch assays are prevalent tool in biomedical studies, however only the wound area is typically measured in these assays. The change in wound area does not reflect the cellular mechanisms that are affected by genetic or pharmacological treatments.

“By analysing the patterns formed by single cells during healing process, we can learn much more on the biological mechanisms influenced by certain genetic or drug treatments than what we can learn from the change in wound area alone.”

Using this technology, the team have already observed that cells respond to wounds by changing their spatial organisation, whereby cells that are more distant from the wound have higher local cell density and are less spread out. Such reorganisation is affected differently when perturbing different cellular mechanisms. This approach can be useful for identifying more specific therapeutic targets and advance our understanding of mechanisms driving cancer invasion.

The team predicts that DeepScratch will prove useful in cancer research that studies changes in cell structures during migration and improve the understanding of various disease processes and engineering regenerative medicine therapies. You can read more about DeepScratch and its applications in a recent study published in Computational and Structural Biotechnology.

About Heba

Dr Heba Sailem is a Sir Henry Wellcome Research Fellow at the Big Data Institute and Institute of Biomedical Engineering at the University of Oxford. Her research is focused on developing intelligent systems that help further biological discoveries in the field of cancer.

Therapeutic potential for breast cancer found in the matrix

Work currently underway in the laboratory of Prof Kim Midwood is investigating the therapeutic anti-cancer potential of tenascin-C, a molecule found in the extracellular matrix of breast cancer