Over its duration, ALTER-brain made major discoveries that are reshaping how scientists and clinicians think about brain metastasis.
Reactive astrocytes and cancer–brain communication
The project mapped, for the first time, the full diversity of astrocytes that react to metastatic cancer. Using advanced single-cell sequencing, the team discovered several new astrocyte subtypes—some protective, others supportive of cancer growth. One key discovery was that a subset of astrocytes uses a molecule called TIMP1 to block the activity of immune cells (CD8⁺ T cells) that normally kill cancer cells. This finding revealed a previously unknown local mechanism of immune suppression in the brain and points to a new way to restore the body’s own defences.
Immune–brain crosstalk and therapeutic targeting
ALTER-brain also identified a special type of brain macrophage marked by CD74, which is reprogrammed by cancer cells through a signaling pathway (MIF–CD74) that activates a pro-tumor program. Blocking this pathway with a drug called ibudilast reduced brain metastases in experimental models, showing that immune rewiring in the brain can be reversed.
Vascular co-option and early metastasis survival
The project further uncovered how cancer cells interact with brain blood vessels during the earliest stages of metastasis. Cancer cells often co-opt existing vessels instead of forming new ones, a process that helps them adapt to the new brain environment and resist therapies. By distinguishing co-opting cells and co-opted endothelium from other vascular types, the project identified potential therapeutic targets to prevent disease progression and relapse.
Cross-cutting platforms and translation to the clinic
Beyond individual discoveries, ALTER-brain produced several tools that are already transforming translational research:
A patient-derived organotypic culture system that allows testing therapies directly on fresh brain tissue, bridging the gap between lab and clinic.
A machine-learning platform to classify brain metastases by their impact on neural circuits, reframing tumor heterogeneity beyond genetics alone.
Identification of a radioresistance mechanism involving S100A9/RAGE, now being tested in a clinical trial (NCT05635734).
Establishment of RENACER, the first national network for brain metastasis research in Spain, linking over 20 hospitals and enabling real patient participation in translational studies.
ALTER-brain delivered all planned objectives, created national infrastructure for collaborative neuro-oncology, and positioned its discoveries for clinical translation.
