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Understanding the Cancer Brain (Professor Justin Stebbing)

I think of cancer cells as having a 'brain', which is responsible for turning the cells "on" or "off". Unlike the human brain, the cancer brain does not have a single location or form. Whilst we can hold certain, physically identifiable, sections of the human brain responsible for particular behaviour types, and perhaps even modify those sections to affect behaviour, the cancer brain is more complex. Rather than manifesting itself as a single mass, the cancer brain is better thought of as a labyrinth of pathways in which an intricate set of chemical reactions between different proteins takes place.

Unfortunately, curing cancer is rarely as simple as identifying the location of cancerous cells and destroying them. If physical destruction of cancer cells was enough to cure cancer, we would be much more effective at doing so. Often we remove entire tumours, only for patients to relapse with either a tumour in the same location, or sometimes in an entirely new location (or locations). This is because the cancer brain is determined to find a way to continue functioning, exploring new pathways and invading and mutating healthy cells.

Escaping the labyrinth

Diagram of the human KinomeIf destroying cancer cells won't beat cancer, what will? We are using an amazing technique called SILAC to gain a comprehensive understanding of the cancer brain, to learn exactly what takes place during the onset and growth of cancer - one protein at a time. Gaining a deep understanding of cancer cells is very difficult, but I believe that as a team, working relentlessly, we can eventually out-think them.

We are studying a type of protein called 'kinases' and the way that they affect other cancer-causing proteins. We know that certain combinations of these kinases and other proteins lead to a mutation of healthy cells into cancer cells but many of these mutations have never been observed, and many of those that have, haven't been adequately understood. Kinases turn other proteins 'on' by a chemical reaction called phosphorylation during which the kinase is like a key and the other protein a lock. The key enters the lock and turns on the other proteins. When you turn on other proteins, cells divide more quickly and this is what occurs when cancers develop and grow. SILAC is an amazing new platform which will allow us to observe and analyse every protein in the cancer cell, one at a time. If one were to study only a single footballer or cricketer, one would not understand the wider context of the game. In much the same way, the kinases in the kinome all work together and interact with other proteins to make a cancer function like a brain so it can behave independently. There are approximately 700 kinases in the human body, so our task is not straight-forward, but there is only one place to start – at the beginning. Previous work on these important cancer-causing proteins have been like studying only the first or second violin in an orchestra – we want to observe the whole orchestra, and the melody it creates.

SILAC explained in more detail

Proteins are present in all of the cells in our body, including in cancer cells. The types of proteins, their quantity, and the level of their activity can differ between normal cells and cancer cells. Proteins enable cancer cells to grow very fast, or they cause them not to respond to a given drug. One of the main approaches in studying cancer cells and identifying new treatment targets is to analyse their protein content in great detail. There are several traditional methods at our disposal, such as a procedure known as western blotting. However, these methods are slow and low throughput. They analyse one protein at a time. Cells contain thousands of proteins so cancer medicine developers like us have been crying out for a more efficient method.

SILAC stands for Stable Isotope Labelling by Amino acids in Cell culture. It is a novel method that allows scientists to perform large-scale identification and quantification of proteins in cells they are studying - in our case, in cancer cells. This method is fast, accurate, straightforward and inexpensive when considering the value of the information it provides.

The scientist grows cancer cells and 'feeds' them a special type of media, which contains amino-acids. The amino acids effectively bind to the proteins within the cancer cells. The SILAC machine is able to detect these amino acids and thus they act as labels for the different proteins within the cell. After being left to grow for three weeks, the cell cultures are collected and a different kinase protein eliminated in each one. (This is done through a simple laboratory technique called 'gene silencing'). This culture is then introduced into a machine which uses the amino acid labels as a means of identifying the different proteins and produces data about them. The data is both quantitative (the machine measures the exact amount of each of the identified proteins) and qualitative, (the machine tells the scientists exactly which proteins are present in the cells).

The delicate balance of proteins in cancer cells is achieved because proteins can 'talk' to one another to influence their activity and quantity, ultimately controlling cancer cell behaviour. This is why it is important to know how eliminating one protein within a cancer cell affects the rest of the proteins and their activity. SILAC enables us to achieve this. We want to eliminate one by one, the kinases in the human kinome, and investigate how abolishment of each one individually affects both the quantity of different proteins within a cancer cell and their activity. This information is crucial for understanding cancer cells - it does not yet exist, and will be pioneering research that generations of scientists will refer to. We hope and expect that it will be a true legacy experiment. This will pave the way for the design of drugs, targeting those proteins that are found to play the most important role in the progression of cancer.