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The behavior of cancer in the brain is a mystery of which little by little science is revealing pieces. When a tumor grew lodged in the cavity of this organ, it did so by pressing on the rest of the tissues around it. This occupation of spaces was assumed as the main reason for the neurological alterations suffered by up to 45% of patients.

And no, it's not. A pioneering study by Spanish researchers has decided that brain tumors do not press with their mass on tissues, but that their cells 'hack' the existing communication between neurons. "This is an important step," says Manuel Valiente, director of the Brain Metastases group at the Spanish National Cancer Research Centre (CNIO). "We would not have managed to successfully pass this proof of concept without the joint work of two disciplines," he insists, referring to the work of the laboratory of Liset Menéndez de la Prida, director of the Neural Circuits Laboratory of the Cajal Institute (CSIC).

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"Together we have managed to answer key questions: why does a small tumor generate large alterations? why does a larger one almost not translate into affectation in the patient?", says Valiente. The researcher emphasizes that they have achieved a scientific basis for the clinical observations they had been collecting. This breakthrough has been the cover of the latest issue of Cancer Cell.

It is that the spread of tumor cells in brain tissue that results in metastasis causes the alteration of brain chemistry. "There are biochemical and molecular alterations made by the tumor and responsible for the modification of the cognitive capacity of patients. We are facing a paradigm shift with implications for diagnosis and treatment," says Valiente.

How have you achieved these results?

The researchers measured the electrical activity of the brains of mice with and without metastases, and observed that the electrophysiological recordings of the animals with cancer are distinct from each other. To make sure that difference is attributable to metastasis, they turned to artificial intelligence. They trained an automatic algorithm with numerous electrophysiological recordings, and in effect the model was able to identify the presence of metastases.

The system even differentiated metastases from different primary tumors, such as skin, lung and breast cancer. These results show that, indeed, metastasis influences brain electrical activity in a specific way, leaving a very clear and recognizable imprint.

Menéndez de la Prida explains the method they have put in place to validate the hypothesis. "Using machine learning we have been able to integrate all the data to create a model that allows us to know whether or not there are metastases in a brain by looking only at its electrical activity. This computational approach could even have the ability to predict subtypes of brain metastases in early stages. It is a totally pioneering work, which opens an unexplored path."

The change of focus provided by this research makes laboratories seek to systematically deepen the cognitive state of patients with brain metastases. "For this, we already have 18 hospitals working in a network. It is something unique in the world," explains Valiente. "Live samples are collected from patients for study, which are housed in the CNIO Biobank."

The researcher adds that the next step they will take is the neurocognitive evaluation of patients. "We will have the opportunity through software to develop a standardized and correlated database that will associate the sample with capabilities. In the laboratory we will be able to measure, in mouse models, the efficacy of the drugs and thus design strategies to be followed later in the healthcare clinic". This will be possible thanks to 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.

Key clues for the development of treatments

Beyond recording changes in brain electrical activity in the presence of metastasis, researchers have also taken the first steps to determine the biochemical changes that would explain this alteration. By analyzing the genes that are 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 palliates the neurocognitive effects of brain metastasis.

Liset Menéndez de la Prida, for her part, will advance in the integration of the recording of brain activity with the analysis of the molecules involved, "to develop new diagnostic probes of brain tumors," he says. It is a task in line with the European project NanoBright, 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 goal is to find drugs that protect the brain from interference created by cancer in neural circuits, using the strategies already mentioned. "We will look for molecules that play a role in metastasis-induced alterations in neuronal communication, and evaluate them as possible therapeutic targets," explains Valiente.

  • cancer