by Daniele Cotton – DPhil Molecular and Cellular Medicine
Punishing fluorescent lights cast a synthetic glow across the corridors of the high-security facility. Armed guards shuffle nervously at their posts. The eerie quiet is broken intermittently by muffled orders on crackly walkie-talkies. Suddenly, a piercing siren fills the silence. Panicked guards march hurriedly to join the search team. But it’s too late. The prisoner is gone. The guards are terrified – this inmate was bad news.
Sounds like the opening of a thriller film, right? It’s also not too far off from what happens in my area of research: cancer metastasis. Cancer is a disease where abnormal cells grow uncontrollably. In the early stages, cancer cells are often confined to a single site, in whichever organ the cancer started. At this point, the cancer cells are like inmates trapped inside a secure prison. They have personal guards (surrounding cells), vigilant patrol officers (immune cells), and barbed wire fences (protein scaffolding) to keep them in place. With so many layers of defence, it might be surprising how often escapes occur. In some cancers, most patients experience metastasis – where cancer cells find their way out of the initial site and seed new tumours elsewhere in the body.
To some extent, it’s a numbers game. A small tumour easily contains billions of cancer cells. With this many inmates, at some point the guards simply become overwhelmed. However, another major factor is at play. In each patient, not all cancer cells are the same. Among the inmates are cells much more dangerous than the others: the criminal masterminds.
Cancer starts as one single cell that replicated itself over and over until it forms a tumour of many billions of cells. However, when we look at a tumour, it is not composed of identical cells. In fact, the diversity is astonishing. But how did this happen?
While cancer grows, the cells fiercely compete for finite resources, such as oxygen and nutrients. This intense competition drives evolution within the tumour. Different cells gain different abilities to give them a competitive edge over their peers, helping them survive the increasingly gruelling conditions.
This is the same concept Darwin proposed for the evolution of life on Earth. Except, instead of over many lifetimes, tumour evolution happens at warp speed. A cancer cell can divide into new offspring several times a day. Together, the sheer number of cells and accelerated evolution leads to the inevitable emergence of an elite group of extremely dangerous cancer cells: masters of deception, disguise, and stealth. These cells smooth-talk the guards into looking the other way, or even lure them in to help them escape. They squeeze through gaps and sneak under the radar. There’s even evidence they contact cells in other organs using extracellular vesicles (a cell’s equivalent of postal mail), recruiting them to create a safehouse for when they arrive.
Understanding metastasis is crucial to combat cancer. The spread of cancer around the body is catastrophic for patients: it is in these individuals that 90% of all cancer-related deaths occur. For the three years of my PhD, I am the warden of a high-security facility of my own. And I’ve been planning a secret mission.
Other investigators focus on studying cells from distant metastases (that is, recapturing escaped prisoners, then examining their behaviour). But there’s a problem here: what if the cells changed their behaviour since they’ve settled into their new environment? They might not be behaving as they did during their escape.
Instead, I aim to trick my most dangerous inmates into handing over their escape plans before they ever get out. I do this by isolating single cancer cells using a specialised robot. I then put them in a ‘Matrix’-style simulation. The simulation is a series of tiny Petri dishes containing different combinations of cells and chemicals that simulate different parts of the body to which the cancer could spread. Unbeknownst to the cell, it’s being monitored the whole time. I record how the cells survive, grow, and interact with other cells. I repeat this process thousands of times and identify the most dangerous cancer cells. I then take this line-up of suspects and use genetic analysis techniques to see exactly what they’re doing beneath the surface. It’s like putting the cells through the most exhaustive interrogation of their life. I can then determine what makes the most harmful cells unique.
Half of us will develop cancer. That’s a lot of prisons that we need to keep airtight. During my PhD, I hope to better understand the cellular and molecular mechanisms that cancer cells use to metastasise. That is, I hope to understand the skillset that allows a mastermind cancer cell to hatch an escape. Once we know exactly how the prisoners are getting out, we can find new ways to stop them in their tracks.