Cancer metastases slowly unveil their weaknesses

From Monday to Wednesday, Barcelona is hosting the scientific conference “Mechanisms of Metastasis”, an event organised by the Institute for Research in Biomedicine (IRB Barcelona) and the BBVA Foundation that brings together a select group of leading international researchers in the field of cancer metastasis.

The organisers of the 32nd Barcelona BioMed Conference, Joan Massagué, director of the Sloan Kettering Institute in New York, Roger Gomis and Salvador Aznar Benitah, both ICREA researchers at IRB Barcelona, all agree that “recent breakthroughs provide an unprecedented opportunity to begin to design treatments that specifically target metastasis.” Most drugs used to treat metastasis are the same ones used for the primary tumour and they are not efficient. The medical, social and scientific impact of metastasis is reflected by the fact that it is responsible for 90% of deaths caused by cancer.

The main advances made regard our understanding of the capacity of metastatic cells to evade the immune system, metabolic perturbations that cancer cells undergo to acquire sufficient energy to become metastatic, and the mechanisms that allow these cells to become dormant until they reactivate and cause tumour growth in distant organs. The scientific breakthroughs made regarding these and other mechanisms associated with the spread of cancer will allow researchers to identify and test potential treatments.

The immune system: an ally that is bypassed

For Joan Massagué, chair of IRB Barcelona’s External Advisory Board, one of the most urgent issues is to determine the role of the immune system: “I believe that metastasis comes about from a clash between malignant regenerative stem cells and the immune system, which is responsible for preventing their survival and growth. When the immune system loses the game, the tumour starts to grow at a distant site. Unravelling how these cells disrupt the immune system is critical,” he says.

One of the most recent developments in immunotherapy has been made by Eduard Batlle ICREA researcher at IRB Barcelona. In a study published in Nature, the scientists have identified the molecule that allows tumour cells to evade the action of the immune system in advanced colon cancer. Moreover, they have reversed the situation, preventing the occurrence of metastasis and curing experimental animal models. “The challenge is now to translate this to clinical practice,” explains Batlle.

Identifying the enemy’s source of energy

“The coming years will bring about significant advances in our understanding of why metastatic cells have a particular metabolism,” says Salvador Aznar Benitah. Cancer cells need a lot of energy to metastasize to distant sites and to acquire genetic alterations that make them stronger. Identifying the alterations that distinguish them from the population of tumour cells that lack invasive capacity is one of the scientific challenges to be tackled. “Once armed with this knowledge, it will be possible to develop treatments that specifically target the metabolic weak spots of metastatic cells,” he explains.

Aznar Benitah may have already found one such weakness. In a study published in Nature, his team reveal that tumour cells are dependent on fats to initiate metastasis and that these fats are absorbed through a protein that is on the tumour cell surface. This protein thus emerges as a potential therapeutic target through which to fight tumour cells. In cooperation with a company in the UK, they are now developing compounds and hope to start clinical assays with patients within 3 to 5 years.

The dormant disease

Many metastatic cells are distributed throughout the body and are asymptomatic for many years before they reactivate and trigger the growth of new tumours. This dormant state is known as latency. Identifying and detecting these cells and finding out how they maintain a dormant state or how they “wake up” may pave the way to treatment opportunities.

In a recent study, Roger Gomis’ team has described a protein that keeps the most common metastatic breast cells dormant. “This finding leads us to consider two plausible options: to identify patients at high and low risk of metastasis and to adjust the treatment on the basis of this risk, or to attempt to mimic the function of the mechanism and thus keep the metastasis latent for longer,” he explains.

Prevention, cure, or chronification?

Will we be able to prevent metastasis, cure it, or turn it into a chronic condition? “All three, in that order,” answers Joan Massagué. As an example, Roger Gomis comments on the early breakthrough made in preventing breast cancer metastasis to the bone. “One of the few specific treatments available is for bone metastases derived from breast cancer tumours,” he explains. “In the lab we identified a protein that distinguishes patients with a higher risk of breast cancer metastasis to the bone. Clinical trials are now underway to see if this treatment for metastasis can be given earlier and thus prevent the spread of cancer,” explains Gomis.

However, the scientists are observing that tumours adapt and become resistant to various treatments and that some tumours already have one or several cells that have become resistant to all types of treatment. “It is clear that scientists working in basic research, clinicians and physicians should work more closely if we are to find a way to prevent metastasis, cure it, or turn it into a chronic condition,” says Aznar Benitah.

“The metastasis challenge: from research to social impact”

On Wednesday evening, after the BioMed Conference has ended, IRB Barcelona has organised a joint event with ESADE to inform non-scientific sectors, such as the business sector, about the problem posed by metastasis, with the aim to explore synergies and speed up advances in this field.

At ESADE, the IRB Barcelona researchers will talk about their breakthroughs and discuss the challenges that face research into metastasis and the impact of metastasis on society. The following figures from the fields of science and innovation will be participating in this event: Joan J. Guinovart, director of IRB Barcelona; Joan Massagué, director of the Sloan Kettering Institute in New York, chair or the External Advisory Board of IRB Barcelona and member of the Board of Trustees of the Barcelona Institute of Science and Technology (BIST); Montserrat Vendrell, partner of Alta Life Sciences; Andreu Mas-Colell, president of BIST; and Francisco Longo, deputy director general of the ESADE Business School, among others.