They discover how breast cancer generates brain metastasis

A large-scale international study has discovered a mechanism that allows breast cancer to metastasize to the brain, a highly lethal phenomenon for which there is currently no effective treatment. The findings could facilitate the development of new drugs and personalized monitoring for early detection and treatment of brain metastases.

This pioneering researchpublished in the magazine Nature Genetics, has been led by Professor Uri Ben-David and Professor Ronit Satchi-Fainaro, together with researchers Kathrin Laue and Sabina Pozzi, from their laboratories at the Gray Faculty of Medical and Health Sciences of Tel Aviv University, in collaboration with dozens of researchers from 14 laboratories in 6 countries (Israel, United States, Italy, Germany, Poland and Australia).

Professor Satchi-Fainaro explains that “Most cancer-related deaths are not caused by the primary tumor, but because of its metastases to vital organs. Among these, brain metastases are among the most deadly and difficult to treat.”

As he points out, “One of the key unresolved questions in cancer research is why certain tumors metastasize to specific organs and not others.. Despite the importance of this phenomenon, very little is known about the factors and mechanisms that make it possible, he acknowledges. “In this study, we join forces to deepen our understanding and search for answers.”

The work, which has received research grants from the “La Caixa” Foundation and the Israel Science Foundation (ISF), the Israel Cancer Research Fund (ICRF), combined two different approaches to cancer research: Professor Satchi-Fainaro’s laboratory, which studies the interactions between cancer cells and their environment (the tumor microenvironment), and Professor Ben-David’s laboratory, which investigates the chromosomal changes that characterize cancer cells.

This complex study involved numerous scientific methods and technologiesincluding the analysis of clinical and genomic data of tumors from breast cancer patients, genetic, biochemical, metabolic and pharmacological experiments in cultured cancer cells, and functional experiments in mice.

Researchers first identified a specific chromosomal alteration in breast cancer cells that predicts a high probability of brain metastases.

“We found that when chromosome 17 in a cancer cell loses one copy of its short arm, the chances of the cell sending metastases to the brain are greatly increased –explains Professor Ben-David–. “We also discovered that the reason for this is the loss of an important gene located in this arm.”

This gene is p53, often called ‘the guardian of the genome’and plays a crucial role in regulating cell growth and division – he continues -. We found that the absence of a functional p53 is essential for the formation and proliferation of cancerous brain metastases. When we injected mouse brains with cancer cells with or without functional p53, we found that cells with disrupted p53 activity thrived much more. “We seek to understand the mechanism that causes this.”

For her part, Professor Satchi-Fainaro explains that “the brain environment is fundamentally different from that of the breastwhere the primary tumor develops, and the question is how a breast cancer cell, adapted to its original environment, can adapt to this foreign environment. “According to our findings, this adaptation is closely related to the alteration of the p53 gene.”

They discovered that p53 regulates the synthesis of fatty acids, a particularly vital metabolic process in the brain environment. “This means that cells with damaged p53, or no p53 at all, produce more fatty acids compared to normal cells, which in turn allows them to grow and divide more quickly in the brain,” he notes.

The next phase of the study focused on components of the brain environment and communication between brain cells and cancer cells. They identified a greater interaction between cancer cells with damaged p53 and astrocytes, brain support cells that secrete substances that help neurons.

In the absence of p53, cancer cells sequester substances secreted by astrocytes and use them to produce fatty acids. Researchers identified a specific enzyme called SCD1a key enzyme in fatty acid synthesis, whose expression and activity are significantly higher in cancer cells with damaged or absent p53.

“Once the mechanism and its key factors have been identified, We seek to use the findings to search for a possible drug against brain metastases –recalls Ben-David–. “We focused on the SCD1 enzyme and evaluated the efficacy of several drugs that inhibit its activity and are currently in development.”

These drugs were initially indicated for other diseases, but they discovered that Inhibition of SCD1 in brain metastatic cells with altered p53 was effective and significantly hindered the development and proliferation of cancerous metastases, both in mice and in samples of brain metastases from women with breast cancer.

The researchers add that Their findings may also help doctors and patients predict disease progression.d, in fact even at an early stage of breast cancer, it is possible to identify if there is a mutation in p53 (or a deletion of the short arm of chromosome 17), which significantly increases the risk of brain metastases later.

For example, doctors could avoid prescribing aggressive biological treatments with serious side effects to patients who do not have a high risk of brain metastases, and opt for aggressive treatment when the risk is high.

Besides, Doctors can tailor monitoring to the patient’s risk levelsuch as performing frequent brain MRIs on patients at increased risk of brain metastases. This type of intensive monitoring would allow for early detection and treatment, significantly increasing the chances of recovery.

“In this study, we joined forces in a broad international effort to address a crucial question: What is the mechanism that allows breast cancer to metastasize to the brain? – the researchers highlight -. We identified several characteristics of cancer cells causally related to this deadly phenomenon, and the findings allowed us propose new drug targets for brain metastasesa condition for which there is currently no effective treatment.”

“In addition, we tested drugs that inhibit a specific metabolic mechanism, SCD1 inhibitors, and found that they are effective against brain metastases. Likewise, Our findings are expected to improve oncologists’ ability to identify high-risk patients. and prepare properly. Although the road ahead is still long, the potential is immense,” they celebrate.