Carlos Martínez, biologist: ‘We want to corner cancer in an evolutionary dead end’

“Cancer is nature out of control,” British oncologist Charles Swanton said in an interview with EL PAÍS, talking about how it follows the same evolutionary laws as living beings, even if it is not. Swanton is one of the lead authors of a study published in the journal Nature on the evolution of lung cancer; using more than 1,600 tumor samples from 421 patients, the TRACERx study seeks to understand how cancer adapts to survive, mutating when treatments threaten its existence or jumping between organs to expand its territory.

One of the main authors among the more than 300 scientists who took part in this study is Carlos Martínez-Ruiz, from the University College London Cancer Institute. This Spanish researcher began his career as an evolutionary biologist at the University of Valencia (Spain), studying ants; then he made the jump to the United Kingdom to apply his knowledge of evolution to cancer. “When I started researching cancer I wondered why progress, in many cases, has been slow, despite all the resources that have been devoted,” he recalls during a video call. “One of the reasons is that tumors are constantly evolving, adapting to therapies and the immune system of patients. General therapies are applied, such as chemotherapy, and the tumors often adapt, become resistant and come back, metastasize and become very hard to stop.”

The project, in which hospitals and universities from all over the U.K. are involved, with funding from charities, recruited patients with early-stage lung tumors. “Tumor samples are extracted from different areas of each patient, and the genetic material is sequenced. In addition, we have tomography and microscopy images we use as a very detailed map of each region of the tumors. Afterward, each patient is followed up and in cases in which there is metastasis or recurrence, a sample of the tumor is extracted and sequenced again,” explains Martínez-Ruiz. Thus, “we have samples of the tumor when it was first discovered and, in some cases, we also have molecular samples of the tumor after it has evolved and developed resistance to treatment,” he adds. With such detailed monitoring, researchers can study the evolutionary history of the tumor and see how it adapted in order to spread. “What the study has shown, in broad terms, is that a greater diversity within tumors at the molecular level tends to result in a poorer survival prognosis and a greater recurrence,” summarizes the researcher.

Question. What is the idea behind these studies on the evolution of lung cancer?

Answer. We want to go to the root of the problem. We wonder how these tumors adapt and where this ability to adapt comes from. The idea of the group that I am in and which has published these articles is that the diversity of the tumor fuels this adaptability. Tumors are not homogeneous, they are made up of many different populations of cells that grow and, as they divide and grow, accumulate mutations, changes in their genetic material. This makes it easier for random alterations to appear, making these cells more resistant to therapies or allowing the tumor to grow faster. We want to understand the origin of this diversity in order to attack it and nip it in the bud. The idea, in the long term, is to know that, if a certain tumor has mutations or molecular characteristics, we can anticipate the next evolutionary step and take it where we want it to go, cornering it, so to speak, in an evolutionary dead end.

Q. Why did you choose lung cancer?

A. Lung cancer kills the most people, in absolute numbers. Furthermore, there has not been a substantial improvement in survival in the last 20 or 30 years, unlike other tumors in which much progress has been made.

Q. Is this lethality of lung cancer due to its biological peculiarities, to a better capacity for adaptation?

A. It’s a combination of many factors, including the fact that many lung cancers are caused by smoking, which produces many mutations and makes those random changes more likely to result in cancer. In addition, these tumors are very diverse, so it is very relevant to study this intratumoral diversity, the multiple populations of cells that coexist in a tumor and give it this ability to adapt. This highly changing genome makes them very interesting for this type of study.

Q. Tumor cells constantly evolve or change the way they evolve, depending on treatments or other circumstances.

A. Before, it was suggested that a mutation could be driving a cell to reproduce uncontrollably and cause cancer, after which the adaptations cease. In this work we do not see that. There are mutations that occur later in the evolution of the tumor that provide it with additional benefits, because there are populations of cells within the tumor that expand more than the rest. Those cells are the ones that usually result in metastasis.

Q. Can this knowledge lead to treatments?

A. This is the basic science part of this work, but it will allow us to focus on cell populations or genetic changes to develop new therapies. Then, at a slightly more immediate level in the clinic, blood samples have been taken from cancer patients looking for fragments of tumor DNA that float freely in the patient’s blood, so to speak. Our group has developed a new computer method that makes it possible to follow the evolution of a tumor through these blood samples, something difficult, because there is usually very little DNA from the tumor, it is very difficult to detect, and it is very difficult to separate it from the rest of the DNA, what would be the background noise. What they have seen is that patients with high diversity in this circulatory DNA at the time of surgery are more likely to develop metastases in the future. That will soon be able to be used to detect high-risk patients.

Q. Cancer is nature out of control, Swanton said, and according to Harold Varmus it is a distorted part of ourselves. How do you see the future of defeating those enemies, so strong and so infiltrated in our nature?

A. I am quite optimistic, mainly because I believe that more appropriate perspectives are now being applied to the treatment of tumors. I’m an evolutionary biologist and I am biased, but I think that applying evolution to the study of tumors is the right thing to do, because tumors kill because they can adapt. We have to understand how they do it.

I think the main reason this hasn’t been done before in a more widespread way is that there was no technology to do it. Sequencing the entire genome of tumors to do these detailed studies, to understand these patterns and to apply it in the clinic, was not cheap. Now, in the clinic, fragments of the tumor genome are sequenced by default, in order to be able to detect some of the specific mutations and apply specific treatments. And the price of sequencing continues to drop, so in the very near future it will be very easy to produce huge amounts of genetic data on a regular basis from any tumor.

The part on which I have worked most extensively, which is RNA, the way cells read the genome, could also be useful. We have looked to see if RNA has specific modifications that later impact the evolution of the tumor. And it does. There are parts of the message that become altered when translated and produce changes that we would not see if we only looked at the genome, the instruction book. So, on one hand, here is an additional source of markers that we can use to try to anticipate the disease, or to detect which patients need which types of treatments. And furthermore, we hope that in the not too distant future, it will also serve to develop targeted treatments. I believe that all of this, I don’t know exactly how, will be a revolution in cancer treatment.

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