Eduard Batlle, molecular biologist: “Tumor cells are accelerated evolution machines”

The place on Earth where it is most difficult to live, says scientist Eduard Batlle (Barcelona, 53 years old), must be “the wall of the intestine.” For everything that circulates out there. From digestion waste to carcinogens that we encounter in the environment or ingest. The researcher knows this hostile environment well: this molecular biologist, director of the Cancer Science Program at the Barcelona Biomedical Research Institute (IRB), has been trying to unravel the functioning of colon cancer for three decades, a tumor that affects almost every year. two million people in the world and causes more than 900,000 deaths.

Ask. Each tumor is a world. What makes the colon different?

Answer. What we have learned is that these tumors are a disease of the stem cells of the intestinal wall: colon cancer adopts the continuous regeneration mechanisms of stem cells. And another central thing that we have learned is cellular plasticity, a mechanism through which tumor cells and normal cells are able to adapt to different types of stimuli or insults.

P. What implications do these characteristics of tumor cells have?

R. This results in them being very plastic tumors and, therefore, when we give them therapy, some cells die, but others simply change their state to adapt to this new situation and resist the treatment. We are beginning to learn what pathways cells use to adapt and what new states they acquire depending on the situation. If we understand this process of adaptability, perhaps we can block it and this would improve therapies very substantially.

P. Are tumor cells smarter than you scientists?

R. Tumor cells are accelerated evolution machines. And, furthermore, this plasticity gives them an additional property that is very difficult to kill. A decade or two ago we had this simplistic idea that blocking an oncogene [forma mutada de un gen que puede provocar cáncer] or by giving a specific therapy we were going to eliminate them, and this is known to be not true. We have to work on other strategies.

“One of the problems that has made us slow down in colon cancer is that we know a lot about the primary disease and very little about metastases.”

P. Is targeting just one goal not enough?

R. No, because cells adapt: if you block a signal, the cells go somewhere else and use another signal or change their state, they disguise themselves, acquire new properties and resist.

P. It’s a little disheartening, isn’t it?

R. From the perspective of attacking these tumors, it greatly complicates the results of the therapies. And this is what we see in the clinic: in colon cancer there have been very few therapeutic advances in recent decades. The standard of treatment is still focused on chemotherapy which, in many cases, is not curative.

P. Does the lack of new drugs have to do only with the biology of the tumor itself or that they cannot find a way to fine-tune their shot?

R. We do not cure because, indeed, it is complex. But, above all, because we don’t understand it well. Much of biology has focused on understanding the primary disease, but metastases, on the other hand, have been studied relatively less because they are much more difficult to access, more heterogeneous… And one of the problems that has made us slow down in cancer of the colon is that we know a lot about the primary disease and very little about the metastases. The biology of the metastasis and the primary tumor are different.

P. How do metastatic cells behave? What is special about them?

R. They are very plastic, they are capable of adopting different states and metastases in different organs behave differently because their microenvironment and the immune system in different organs is different. And this means that many times, for example, a patient is given therapy and there are metastases that respond and others that do not. And we still don’t fully understand what the differences are.

Eduard Batlle, in the gardens of the Barcelona Biomedical Research Institute (IRB), where he serves as director of the Cancer Science Program. Maximilian Minocri

P. His team discovered malignant cells that break off from the cancer and spread. What has this study meant?

R. The focus of this article was to study the invisible phase of the disease [metastásica]: In the majority of colon cancer patients, the diagnosis occurs at a time when there is still no metastasis and they undergo surgery on the primary tumor, but around 30% of patients relapse because this residual disease exists. The primary tumor has spread, emitting cells that act like seeds that remain anchored to our organs. They are invisible, we cannot detect them and, eventually, they suppress growth and generate metastases. Our focus was to understand what happens there, what these cells are, where they are, what genetic elements make them up and, of course, how we can eliminate them.

P. So, is it possible that, when the primary tumor is detected, there may already be metastatic cells, even if they are not seen?

R. There are micrometastases or residual disease, which are invisible and we cannot detect them with the methods we have today. The patient appears to be disease-free, but we know that he is at risk of relapse and developing it more aggressively. There is a possibility that during surgery some of these cells may escape, but this probably happens in a very small fraction of cases. In most cases, the dissemination phenomenon has occurred before diagnosis, but we do not fully understand whether it was a week before, a month before, or two years before.

P. Is this invisible phase of the metastatic process applicable to other tumors?

R. Yes, this process happens in all tumors that metastasize. One of the new concepts that we propose is that as the metastasis expands, the tumor microenvironment matures. And we think that this process offers different therapeutic windows: there may be effective therapies for micrometastases that then stop working in larger ones or macrometastases. For example, we know that when metastases have expanded, immunotherapy does not work.

P. Is the idea to advance immunotherapy to very primary phases of the disease to avoid metastases?

R. Yes, do it preventively. Our research revealed that, when metastases are very small and the tumor microenvironment is immature, immunotherapy is effective. And in experimental models we test neoadjuvant therapy, before surgery, and this immunotherapy activates the immune system systemically. It looks for those residual cells that are hidden in our organs and eliminates them before they can generate metastases. I suspect that this type of treatment is going to prevail for many types of cancer because it is relatively safe, it will not be tremendously expensive and we are convinced that it will have a therapeutic effect to prevent relapses in patients with localized disease.

There is a terrible epidemic of colon cancer in young people”

P. What happens to patients who are already diagnosed with metastasis?

R. Metastases when they are already established are very complex. In colon cancer, more and more attempts are also being made to operate on metastases. But metastatic disease, in general, is a systemic disease, each organ can have more than one metastasis, they are usually heterogeneous and respond differently to therapies. Later, many times, when the disease is very advanced, there are systemic effects throughout the body that make it very difficult to cure these patients. Furthermore, these metastases constantly evolve and adapt to therapy.

P. Are metastases the beginning of the end?

R. For some types of tumor this is bad news, but for others, there is more hope. 95% of patients who die from cancer die from metastases. They have a very poor prognosis, in general. But, today, for some types of tumors, such as metastatic melanoma, in many cases we can cure them with immunotherapy. There have been very important advances: breast cancer is a paradigm of how therapies are capable of making cancer chronic. But this, in colon cancer, does not exist: we do not have therapeutic tools that allow us to make metastases chronic.

P. Colon cancer is increasing in young people and decreasing in older people. Because?

R. It is decreasing in the elderly and, in part, it is believed – although there is controversy – that it is because there are screenings. But there is an epidemic of colon cancer in young people, which is terrible. We do not know why. Everyone reasonably suspects that it has to do with something we are doing today that we didn’t do before. It could be anything from changes in the diet to some type of additive, plastics… We don’t know, but it is a very relevant topic. What we know is that colon cancers in young people are very similar, at a molecular level, to colon cancers in adults. That is to say, it is not that it is a different disease, but that, for some reason, the disease happens earlier. There is something that our young people are doing that predisposes them.