A pioneering study discovers that brain tumors 'hack' the communication between neurons

Almost half of patients with brain metastasis have their cognitive capacity affected. Until now, it was assumed that this is due to the physical presence of the tumor, which puts pressure on the neuronal tissue. But something is wrong with that hypothesis. mass effect of the tumor, because there is often no relationship between the size of the cancer and its cognitive impact. Small tumors can generate important alterations, and vice versa. Because? The explanation may be that brain metastasis hack brain activity, as demonstrated for the first time by a study published in Cancer Cell to which the magazine has given its cover in the printed edition.

The authors, from the Higher Council for Scientific Research (CSIC) and the National Cancer Research Center (CNIO), have discovered that when cancer spreads in the brain (metastasizes) it alters brain chemistry, and thus interferes with neuronal communication. -neurons communicate through electrical impulses that are generated and transmitted through biochemical changes in the cells and their environment.

The laboratories of Manuel Valiente (CNIO) and Liset Menendez de La Prida (Cajal Institute of the CSIC) within the European project NanoBright, aimed at developing new technologies for the study of the brain, and with the participation of other funding agencies such as MICINN, AECC, ERC, NIH and EMBO.

Demonstration with artificial intelligence

The researchers measured the electrical activity of the brain of mice with and without metastasis, and observed that the electrophysiological recordings of animals with cancer are different. To ensure that this difference is attributable to metastasis, they turned to artificial intelligence. They trained an artificial intelligence system with numerous electrophysiological recordings and, indeed, the model learned to identify the presence of metastases.

These results show that metastasis influences brain electrical activity specifically, leaving a very clear imprint.

The study represents, for the authors, a “paradigm change” in the basic knowledge about how brain metastasis develops, and has implications for the prevention, early diagnosis and treatment of this pathology.

On the trail of a drug against neurocognitive effects

In addition to recording changes in brain electrical activity in the presence of metastases, researchers have begun to explore the biochemical changes that would explain this alteration. By analyzing the genes that are being expressed in the affected tissues, they have identified a molecule, EGR1, with a potentially important role in the process. The finding opens the possibility of designing a drug that prevents or alleviates the neurocognitive effects of brain metastasis.

As Brave, director of the group of Brain Metastasis from the CNIO, “our multidisciplinary study questions the hitherto accepted fact that neurological dysfunction, very common in patients with brain metastasis, is due solely to the mass effect of the tumor. We propose that these symptoms are a consequence of changes in brain activity resulting from biochemical and molecular alterations induced by the tumor. “It is a paradigm shift that could have relevant implications for diagnosis and therapeutic strategies.”

Liset Menendez de La Prida, director of the Neural Circuits Laboratory of the Cajal Institute (CSIC), points out: “Through machine learning we have been able to integrate all the data to create a model that allows us to know whether or not there is brain metastasis by looking only at the electrical activity. This computational approach could even have the ability to predict subtypes of brain metastasis in early stages. It is a totally pioneering work, which opens an unexplored path.”

Both authors highlight the multidisciplinary nature of a complex work that combines neuroscience, oncological and computational research, and each of these areas with, in turn, a wide range of different techniques.

Cognitive study of patients and development of non-invasive techniques

The change in focus brought about by this result makes researchers want to analyze the cognitive status of patients with brain metastasis much more systematically. This is, for Brave, one of the main next steps. For this it will be key BE REBORN, the National Brain Metastasis Network promoted by the CNIO, which has already served to generate the largest collection of live brain metastasis samples in the world (with the consent of the patients, the samples extracted in the operating room are made available to the international scientific community in the CNIO Biobank), and in which they are now going to introduce neurocognitive evaluation protocols for participating patients.

Menendez de La Prida, for its part, will advance in the integration of the recording of brain activity with the analysis of the molecules involved, “to develop new diagnostic probes for brain tumors,” he points out. It is a task in line with the European NanoBright project, which seeks to create non-invasive techniques to investigate the brain and treat its pathologies, and in which the CSIC and the CNIO participate.

Another objective is to find drugs that protect the brain from the interference created by cancer in neuronal circuits using the novel strategies already mentioned. “We will look for molecules that play a role in metastasis-induced alterations in neuronal communication, and we will evaluate them as possible therapeutic targets,” he explains. Brave. In addition to the artificial intelligence devised by the CSIC team, they will use the METPlatform technology developed at the CNIO to evaluate the possible therapeutic activity of hundreds of compounds at a time on brain tissue samples affected by metastasis.

Source: CSIC