Researchers from Tel Aviv University have identified a link between loss of p53 activity (and sometimes deletions in the short arm of chromosome 17) and the adaptation of breast cancer cells to the brain environment through fatty acid pathways and communication with astrocytes, and have pointed to inhibition of the SCD1 enzyme as a promising therapeutic direction.
A large-scale international study, led by researchers from Tel Aviv University's Gray Faculty of Medicine and Health Sciences, has revealed a mechanism that allows breast cancer to metastasize to the brain – a highly lethal phenomenon that to date has no effective treatment. The findings may enable the development of new drugs as well as personalized monitoring for the early detection and treatment of brain metastases.
The groundbreaking study was led by Prof. Uri Ben-David and Prof. Ronit Sacchi-Painero, and researchers Dr. Catherine Lau and Dr. Sabina Pozzi from their laboratories at the Grey Faculty of Medicine and Health Sciences at Tel Aviv University, in collaboration with dozens of researchers from 14 laboratories in 6 countries (Israel, USA, Italy, Germany, Poland and Australia). The article was published in the journal Nature Genetics.
Prof. Sacchi-Painero explains: "Most deaths in cancer patients are not caused by the primary tumor but by the metastases it sends to vital organs. Of these, brain metastases are among the deadliest and most difficult to treat. One of the most important and unresolved questions in cancer research is why certain tumors send metastases to specific organs and not others. Despite the importance of the phenomenon, very little is known about the factors and mechanisms that enable it. In this study, we joined forces to deepen our understanding and seek answers."
The current study combined two different approaches to cancer research – Prof. Sacchi-Painero's laboratory, which studies the connections between cancer cells and their environment in the body (microenvironment), and Prof. Ben-David's laboratory, which studies chromosomal changes that characterize cancer cells. As part of the complex study, the researchers used a large number of scientific methods and technologies: analysis of clinical and genomic data from cancer patients, genetic, biochemical, metabolic and pharmacological experiments on cancer cells in culture, and functional experiments in mice.
First, the researchers discovered a specific chromosomal change in breast cancer cells that predicts a high chance of brain metastases. Prof. Ben-David explains: "We found that when chromosome number 17 in a cancer cell loses a copy of its short arm, the chances of the cell sending metastases to the brain increase. We also revealed that the reason for this is the loss of an important gene located on this arm. This gene is p53, which has been nicknamed the 'guardian of the genome,' and plays an important role in controlling the growth and division of cells. We discovered that the absence of normal p53 is necessary for the formation and proliferation of cancer metastases in the brain. When we injected cancer cells with and without normal p53 into the brains of mice, we found that the cells in which we had damaged the gene's activity proliferated much more. We wanted to find out what the mechanism was that caused this."
Prof. Sacchi-Painero adds: "The brain environment is fundamentally different from the breast environment of the primary tumor, and the question is how a breast cancer cell, adapted to this environment, can adapt to the foreign brain environment. According to our findings, this adaptation is closely linked to damage to the p53 gene. We found that p53 controls the production of fatty acids, a metabolic process that is particularly essential in the brain environment. This means that cells in which p53 is missing or damaged produce more fatty acids compared to normal cells, and as a result are able to grow and divide faster in the brain."
Next, the researchers focused on the components of the brain environment, and on the communication between brain cells and cancer cells. They identified increased communication between cancer cells with damaged p53 and astrocytes – support cells in the brain that secrete substances that help neurons. In the absence of p53, cancer cells take over the substances secreted by astrocytes and use them – to produce fatty acids. The researchers identified a specific enzyme called SCD1 – a key enzyme in the production of fatty acids – whose expression levels and activity are higher in cancer cells where p53 is damaged or missing.
Prof. Ben-David: "After revealing the mechanism and the key players, we sought to use the findings to search for a potential cure for brain metastases. We chose to focus on the SCD1 enzyme and tested the efficacy of several drugs that inhibit its activity and are in development. These drugs were originally intended for other diseases, but we found that inhibiting SCD1 in metastatic cells with damaged p53 is effective, and significantly impairs the development of cancer metastases – both in mice and in samples from brain metastases from women with breast cancer."
The researchers add that their findings may also help doctors and patients in terms of predicting the development of the disease: Already at an early stage of breast cancer, it is possible to identify whether cells have a mutation in the p53 gene (or a deletion of the short arm of chromosome 17), which significantly increases the risk of brain metastases later on. For example, doctors will be able to avoid administering aggressive biological drugs with severe side effects to patients who are not at high risk of brain metastases, and, on the other hand, prefer aggressive treatment when the risk of brain metastases is increased. In addition, the treating physician will be able to perform monitoring that is tailored to the patient's risk level - such as periodic head MRI examinations for a patient at increased risk of brain metastases. This type of intensive monitoring will enable early detection and treatment that will significantly increase the chances of recovery.
The researchers conclude: "In this study, we joined forces in a broad international effort to answer a very important question: What is the mechanism that allows breast cancer to metastasize to the brain? We found several characteristics of cancer cells that are causally linked to this deadly phenomenon, and the findings allowed us to suggest new targets for developing drugs for brain metastases - a phenomenon for which no effective treatment has been found to date. Furthermore, we examined drugs that target a specific metabolic mechanism, SCD1 inhibitors, and found that they are effective for brain metastases. In addition, our findings are expected to increase the ability of oncologists to predict which patients are at increased risk, and to prepare accordingly. Although there is still a long way to go, the potential is enormous."
The project is supported by competitive research grants from the Israel Science Foundation (ISF), the Israel Cancer Research Foundation (ICRF), and the Spanish bank Fundacion “La Caixa”. It is also part of a larger research project being carried out in Prof. Sacchi-Painero’s laboratory, supported by an Advanced grant from the European Research Council (ERC), an ERC Proof of Concept (PoC), and the Kahn Foundation, as well as part of a larger research project being carried out in Prof. Ben-David’s laboratory, supported by a Starting grant from the European Research Council (ERC).
More of the topic in Hayadan:
2 תגובות
I checked. It seems fine to me, probably a glitch in your browser.
The page is aligned to the left and is illegible.