09 December 2021
Ana Luisa Correia
Keeping dormant cancer cells asleep.
Nearly all types of cancers have the potential to form metastatic growths. However, the exact moment when metastasis emerges is highly variable. While some patients develop metastatic disease soon after the primary tumour appears, others can see decades pass before it happens. What is the source of this variability?
Ana Luisa Correia, a new faculty member at Champalimaud Research, has an answer. In this interview, she tells us about her groundbreaking findings and how she intends to translate them into novel anti-metastatic treatments.
You've just returned to Portugal after spending over a decade developing your scientific career abroad. How did this experience shape your current scientific approach?
I was born in the centre of the Douro valley, in a small town called Lamego. I decided early on that I wanted to be a biologist, so I joined the GABBA graduate programme. We could go anywhere in the world for our PhDs, and I chose to go to Berkeley, California, to the lab of Mina Bissell, a pioneer in the field of Cancer.
In my PhD project, I investigated how a specific molecule controls the invasion of new cells into the developing breast. Even though this is a natural developmental process, it is relevant for cancer research because it can be hijacked by tumour cells. Indeed, my results revealed why drugs that target this molecule have failed dramatically to prevent tumour cells from invading the breast in cancer patients.
My experience at Berkeley was amazing. At first, it was a bit of a shock. I was always one of the best students back in Portugal, but there I was just one of many. Anything felt possible at Berkeley, and it was inspiring to be surrounded by so many curious, driven and enthusiastic individuals. Being immersed in that atmosphere really pushed me forward, and I think it shaped the scientist I am today to a large degree.
After graduating, I decided to re-establish my roots back in Europe. I joined Mohamed Bentires-Alj's group in Switzerland, where I received external funds to support my postdoctoral research, including an EMBO Long-Term Fellowship and a grant from the University of Basel.
Can you tell us about your postdoctoral project?
I wanted to understand how breast cancer spreads to other organs. What really puzzled me was that while some patients develop metastatic disease soon after the primary tumour is found, others can go 10, 20, or even 30 years before being diagnosed with metastasis.
At the root of this phenomenon are cancer cells that break away from the primary tumour and migrate to other organs, where they remain dormant. This is a common evolutionary strategy that organisms carry out when they find themselves in sub-optimal growth conditions. An example of that are animals that go into hibernation. They essentially pause until the situation improves. Cancer cells do precisely the same, and I was interested in figuring out why they become dormant and what causes them to wake up.
How did you investigate these questions, and what did you find?
The main challenge was to find dormant cancer cells inside a living organism. At the time, we didn't have the tools to observe these cells in mice, which is the animal model I use in my research. To solve this problem, I leveraged the fact that non-dormant cancer cells naturally divide at a high rate. And so, I developed a molecular tool that detects non-dividing cancer cells. A kind of a “dormant cancer cell reporter”.
With this tracker, I found that the liver was the tissue that had the highest number of dormant cancer cells. This location was not surprising since the liver is one of the main sites of breast cancer metastasis. And because the liver is an essential organ, which is very difficult to treat, liver metastasis is a leading cause of death among breast cancer patients. Once I had a way to visualise dormant cells, I could finally ask what keeps these cells asleep.
The answer was Natural Killer Cells. I like to call them "our first responders against invading tumour cells" because they can kill cancer cells without priming or prior activation. Our results showed that when an animal had enough Natural Killer cells in the liver, they would control the disease by pushing cancer cells into dormancy.
What could cause the number of Natural Killer cells to change?
We know that the environment in each organ plays a role in controlling the number of these cells. Specifically, in this project, I discovered a mechanism by which injury activates cells [called hepatic stellate cells] in the liver. These cells then produce a molecule that binds to Natural Killer cells and restricts their proliferation, effectively limiting their number in the tissue.
In addition to trauma, certain conditions also negatively affect Natural Killer cells by injuring the liver. These include, for example, non-alcoholic fatty liver disease, which is caused by an individual's diet, and chemotherapy. Though chemotherapy is a life-saving drug that increases the lifespan of patients, we now have data demonstrating that it could be toxic to specific organs. So, unfortunately, the same drug that would eliminate active tumours might indirectly facilitate metastatic growth. One of the research avenues I intend to follow is to look for ways to reverse the injury effects caused by chemotherapy, thereby maximising the benefits of the treatment without incurring a risk of developing metastasis.
Did your findings lead to potential therapeutic avenues?
Yes, actually, this was really cool. Not only did we identify several potential targets, but we can even test them relatively quickly since approved drugs against these targets already exist. Moreover, in the study, we proved the efficacy of one of them in mice. This therapy, which is based on the action of a molecule called IL-15, expanded the pool of Natural Killer cells, significantly reduced the overall metastatic burden, and completely prevented metastases in the liver, though it didn't eliminate the dormant tumour cell reservoir.
Remarkably, this treatment translated into a significant extension of mouse survival. This provides a proof of concept, showing that therapies aimed at normalising the Natural Killer cell numbers might prevent metastatic disease. IL-15 drugs are considered well-tolerated and safe, but we still don't have data on their effects when taken chronically, as might be needed for these patients.
We are also engaged in a clinical research programme with clinicians at the University Hospital of Basel. We plan to start two clinical trials. The first will trace the levels of Natural Killer cells in breast cancer patients at high risk of developing metastasis, and examine whether those levels correlate with the prognosis and the outcome of these patients. And the second would be an intervention trial where we would boost the numbers of Natural Killer cells using IL-15 drugs.
How are you planning to further develop this work at Champalimaud?
The most immediate thing I want to do is understand more deeply what determines the number and performance of Natural Killer cells in tissues. Then, as a second step, I want to study how variables that organisms are exposed to, such as diet and chemotherapy, challenge this immunity.
We will initially study these questions in the mouse animal model, which is a good surrogate for human breast cancer. Still, the lab's goal is to conduct fundamental research with an enduring vision towards moving up to the clinic. Since Champalimaud has a clinical centre, I am really looking forward to working in close collaboration with our clinicians so together we can speed up the translation process.
One of the more challenging aspects of this work is that some patients and clinicians are sceptical about studying something that isn't a disease yet. But so many years of research have shown that metastasis is extremely difficult to treat, and that if you wait until it emerges, treatment might not even be effective. So my research is really an invitation for a change in concept. I firmly believe that by pursuing this approach, we have a chance of winning the battle by preventing metastasis from happening in the first place. But as we all know, anything that involves change requires time.
