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Stopping breast cancer spread

Despite the remarkable advances towards understanding breast cancer, most breast cancer related deaths are due to the onset of distant metastases (the spreading of cancer cells to form secondary tumours around the body) and a poor response to current therapies. One subtype of breast cancer, called triple negative breast cancer, has a particularly high frequency of spreading and poor response to standard therapies. This subtype represents ~15% of all breast cancers, and has the worst outcome, making the development of new treatment strategies is a priority.

Professor Morag Park explains “We have identified an alteration found in 60% of this subtype of breast cancer that contributes to cancer spread. This project aims to understand the mechanism through which this change, involving loss of function of a gene called Kibra, causes the disease to spread. We have developed mouse models that accurately mimic human breast cancer that lack the Kibra gene. We will identify how Kibra acts to stop breast cancer spread and how its loss enhances tumour cell invasion into neighbouring tissues. Our ultimate goal is to develop new therapeutic strategies to treat patients with triple negative breast cancer.”

Understanding exactly how invasive breast cancer cells break free

Dr Chavrier is working to understand how invasive breast cancer spreads around the body.

Breast cancer which has developed the ability to spread away from the original tumour is much more difficult to treat, and outlook for the patient is worse. But before they can develop new treatments targeting invasive breast cancer, scientists need to understand how breast cancer cells break away in the first place.

Dr Chavrier and his team already know that a specific cell protein on the surface of invasive breast cancer cells can perforate surrounding cell layers and form ‘tunnels’- helping the cancer cell escape away to other parts of the body. And they recently found that it is the nucleus- the cell command centre- which gives the order for the protein to act.

In this project the researchers will now investigate exactly how and why the nucleus makes this command, and what other proteins are involved in helping invasive breast cancer cells break free.

“We believe that this work will help inform development of future breast cancer treatments, and will ultimately help breast cancer patients” says Dr Chavrier.

How can short strings of nucleic acid lead to breast cancer drug resistance?

Breast cancer is the most common cancer worldwide and it claims more than half a million lives each year. Among the greatest challenges in its treatment is the resistance of some tumours or to chemotherapy. This often happens because the cancer increases the abundance of molecules that can inactivate the drug or expel it from the cell.

Dr Anna Git is studying RNA, a temporary copy of a small section of DNA, usually encoding instructions to make proteins. She told us "Some short RNAs, such as Vault RNAs (vtRNAs) do not code for protein, but are instead functional themselves. Of the four vtRNA types in the human genome, one can directly halt the growth of cancer cells. Two other types can attach to and seclude certain chemotherapeutic drugs, thus preventing their activity. Encouraging results have shown showed that altering the amount of vtRNAs in some lab-grown cancer cells substantially altered the cells' response to chemotherapy.

She explained "With my grant I propose to test how vtRNAs attach to a broad selection of drugs. I will also alter vtRNA levels inside cells to affect drug resistance in models of different types of breast cancer. Finally, I will identify proteins that recognise vtRNAs to understand how vtRNAs lead to drug resistance. In the future, I hope to help predict this mode of drug resistance in patients and perhaps avoid it altogether."

Why this research is important:

Chemotherapy remains our best weapon against many aggressive or advanced cancers. Unfortunately, the side effects of chemotherapy lay a heavy physiological, psychological and social burden on the patients and their families. If the tumour is resistant to the treatment, this burden is suffered in vain. While medical science has come a long way in understanding how chemotherapy works, we know far less about why it sometimes doesn’t. I hope that if I help understand which tumours are resistant to which chemotherapy I can help improve many patients’ quality of life by avoiding futile toxicity and allowing the earlier application of alternative treatments.

How does obesity increase the risk of cancer spread?

Being very overweight is linked to an increased risk of developing cancer, but researchers don’t yet know exactly why this is. Dr Hector Peinado Selgas and his team in Madrid have an idea, and they are using their Worldwide Cancer Research funding to investigate.

“Obesity is fast becoming a major problem for humankind.” Says Dr Peinado Selgas. “An obese person is more likely to develop cancers such as bowel cancer, breast cancer, and ovarian cancer. We want to map the biological processes which link obesity to cancer progression and cancer spread.”

“We already have data which hint that tumour cells and fat cells send small ‘parcels’, known as exosomes, to communicate with each other. In this new project we want to study how this exosome-based cross-talk could increase the risk of the cancer spreading.”

Dr Peinado Selgas and his team will use patient samples to investigate how the chemical make-up of the exosome parcels change depending on patient obesity and how their cancer progresses. “We can detect traces of these exosomes in the blood,” says Dr Peinado Selgas, “so ultimately we want to see if we can define specific exosome ‘signatures’ that might give a clue to how and when a person’s cancer might spread. This will also help us design new therapies to target the pathways which regulate cancer growth and spread.”

New year, new research

We support research into all cancer types and this latest grant round was no exception. The projects contain a good mix of cancer types from mouth and lip to breast, lung, pancreatic, lymphoma and liver cancer to name but a few. And of course a large amount is being spent on understanding the very fundamental principles behind how our cells behave and what goes wrong in cancer. Keeping with our ethos of supporting the best research around the globe, the projects are taking place all over the world including England, Portugal, Greece, Spain, Australia, The Netherlands, France, Germany, USA and Canada.

Opening up about mouth cancer

Some of the projects that most excite us are Dr Guy Lyons from the University of Sydney, Australia. He is identifying genetic changes that occur when mouth cancer starts so that it can be diagnosed early, when treatment is more likely to be successful. You can read more about mouth cancer in our recent blog. Dr Lyons told us “The support of organisations such as Worldwide Cancer Research for research into the fundamental biology of cancer is essential for the discovery of new paradigms that enable new approaches in the clinic down the track.”

Developing new ‘super cameras’

Professor Carolyn Moores at Birkbeck University of London in England is developing state of the art electron microscopy to actually visualise where drugs bind (stick) to their target molecules inside the cancer cells. This is VERY cool.  She said “Revolutionary new imaging technology means that our pictures will provide unprecedented detail, from which we will calculate the three-dimensional shape of our samples. This technique could potentially revolutionise the way drug discovery is carried out and our findings could be used to design specific drugs that can be further developed to improve treatments for cancers in the future. It is an exciting time to be an electron microscopist and we are thrilled that Worldwide Cancer Research is supporting our research in this area.”

Studying ‘bubbles’ to beating childhood brain cancer

We are also funding Dr Kasper Rouschop at Maastricht University in The Netherlands (pictured above) who is studying how ‘bubbles’ released by glioblastoma tumours encourage blood vessels to grow into the tumour. Glioblastoma’s are a type of brain tumour that commonly effects.  He told us “We anticipate that the results of this research will enable us to evaluate whether targeting these particular bubbles could be a potential new way to reduce the growth of brain tumours.  Our approach is highly innovative and is based on our previous identification of “bubbles” that are specifically released by hypoxic tumour cells. Without the support of Worldwide Cancer Research, evaluation of this promising approach would not be possible.”

And last, but by no means marking the end of my list of fab new projects, is Dr Ruben van Boxtel at the Hubrecht Institute in the Netherlands. He is trying to figure out why cancer arises in some parts of the body more than others. Great question to try to answer!

Our next grant round is already underway and our Scientific Committee will meet in March to decide who gets funded.  But this relies on donations, no money means no research.  If you would like to join team Worldwide Cancer Research and make a donation today just text WORLDWIDE to 70004 to donate £10. Thank you.

Image kindly provided by Dr Kasper Rouchop.

Watching (cancer) stem cell behaviour in genetic mouse models

Almost all normal tissues within our bodies have a tiny population of stem cells. Stem cells are a kind of 'starter cell' which can multiply and change into a wide variety of other cells depending on where they are located in the body. Stem cells are essential for our body's tissues to maintain themselves and repair. For cells to become cancer cells, several genetic mutations have to happen within that stem cell. As stem cells and cancer stem cells live for a long time, it is thought that they are the ideal cells in which several mutations could happen.

More recently, scientists have suggested that stem cells may lose some of the unique stem cell properties, and that they may even be replaced, within tissues, by cells that have become specialised cell types. It is thought that these cells revert back to stem cells. 

Dr van Rheenen and his team have developed state-of-the-art microscope technology which enables them to study live stem cells, in real time, to watch what they are doing as tumours develop and grow. They will use mice in which the stem cells, from healthy and cancerous bowel and breast tissues, have been genetically modified to be fluorescent so that they are able to watch what happens to these stem cells, as it happens within the mice, over a period of several weeks. They want to find out whether specific changes occur to the stem cells, and where they happen within tissues, as well as whether the stem cells are able to move about within tissues. They will also be looking to find out whether the number of stem cells within the tissues changes over time, and what role the suspected changes may play in the spread of tumours to other parts of the body. This study will answer some important questions about how stem cells contribute to cancer.

Understanding the role of LOXL2 in the development of skin and breast cancer

One of the main factors making tumours so dangerous is their ability to invade surrounding tissues and organs and spread throughout the body. This is known as metastasis. Individual cancer cells squeeze between the normal cells nearby and push their way through the tissue. They are then carried in the blood stream and can form new tumours in other parts of the body, known as secondary tumours or metastases. In the last decade, significant findings have shed some light on the processes that enable cancer cells to spread. This involved the identification of key molecules for tumour spread.

Professor Cano's research team have previously described the interactions of some of these molecules with a molecule called LOXL2. She will be using her Worldwide Cancer Research grant to reveal the role of a molecule called LOXL2 in tumour development and metastasis. The work will mainly focus on breast and skin tumours.

Creating new antibodies to overcome drug resistance in HER2-positive breast cancer

In about a quarter of women with breast cancer, the cancer cells have a very high level of a protein called HER2 on their surface; this is referred to as HER2-positive breast cancer. As the HER2 protein helps cancer cells to grow, a number of drugs have been developed to stop HER2 from working properly. One such drug, Herceptin, uses a molecule called an antibody that attaches to the HER2 protein, blocking its action and stopping the cancer cell from growing. Unfortunately, cancer cells can become resistant to this treatment. Research suggests that when HER2 is blocked it causes an increase in the level of a similar protein, called HER3, on the cancer cell surface, and that this is a major cause of resistance. Scientists are now trying to find ways to block HER3 along with HER2, thereby providing a way to treat tumours that have become resistant to Herceptin. A special type of antibody has been discovered in sharks; it has a smaller attachment region than human antibodies and so can block its target in a very different way. For this reason scientists believe shark antibodies may work better than the current antibodies for the treatment of HER2-positive breast cancer. Dr Dooley and her team have been awarded a grant from Worldwide Cancer Research to find shark antibodies that can attach to the HER2 and HER3 proteins and stop them both from working. They will then investigate whether these antibodies can stop cancer cells from growing, using lab-based tests.

Investigating the role of podoplanin in allowing breast cancer to spread

The cancer microenvironment consists of the space in between the cancer cells within the tumour mass. Among other components, it contains cells of the immune system including some cells called macrophages.  These immune system cells are produced in order to attack the tumour and try to destroy it. However, in some types of cancer, such as breast cancer, the cancer cells "convince" immune cells to work for their own benefit, favouring tumour growth and spread.  One of the things that makes cancer so dangerous is this ability to grow and spread away from the original tumour and into surrounding tissues and organs.  These secondary tumours can stop key organs from working which can make successful treatment much more difficult.

In an initial study Professor Mazzone and his team have found that, when exposed to a tumour like environment, macrophages are able to regulate many things, including levels of a molecule called podoplanin.  Podoplanin is known to be found at high levels in cancer cells.  Professor Mazzone is now using his Worldwide Cancer Research grant to better understand the role of podoplanin in breast cancer, with a particular focus on the part played by macrophages in allowing the cancer cells to invade the lymphatic system and spread.  The team will start their work using cells grown in the laboratory but will then use mouse models, some with podoplanin and some without.  Using mouse models like these are essential to study how cells can move around the body.  Professor Mazzone hopes that his findings will shed new light on how breast cancer cells can spread which, in the future, could possibly help with the development of new treatments to stop this process.

Studying the role of progesterone and synthetic progesterone in breast cancer

Progesterone is a hormone produced by the ovaries.   It is essential for the development and function of the female breasts and reproductive system and has a wide range of effects in these tissues.  During the menopause some hormones, including progesterone, are no longer produced.

Hormone replacement therapy (HRT), used to reduce the symptoms of menopause, replaces these missing hormones, including a synthetic version of progesterone, called a progestin.  However, progestin in HRT increases a woman’s risk of breast cancer.  Progesterone sticks to a molecule called a receptor (PR) within a cell.  There are two types of progesterone receptor, PRA and PRB, which are found in normal cells.  In the early stages of breast cancer there are much higher numbers of PRA and PRB in breast cancer cells. When progesterone sticks to PRA or PRB the receptor attaches itself to specific sequences of DNA and controls the activity of key genes.  The types of DNA sequences that PR binds to is also different in normal breast cells compared to cancerous cells.  Professor Clarke and her team have found that the DNA sequences are different again when progestins from HRT attach to the receptor. They plan to use their Worldwide Cancer Research grant to study well defined models of breast cancer and normal breast tissue to identify what causes PRA and PRB to interact differently with DNA in the breast, as well as studying the role of progestins from HRT in increasing the risk of breast cancer.