Periodic Reporting for period 4 - ALTER-brain (Metastasis-associated altered molecular patterns in the brain)
Berichtszeitraum: 2025-01-01 bis 2025-06-30
Cancer that spreads to the brain—known as brain metastasis—is one of the most devastating complications of cancer. It affects hundreds of thousands of patients each year, yet remains extremely difficult to treat. Unlike the original tumor, a brain metastasis must adapt to an entirely new and highly specialized organ. The surrounding brain tissue, made up of neurons, blood vessels, and support cells called astrocytes, reacts strongly to the invading cancer. These reactions can either limit or promote tumor growth, but how they do so has been poorly understood.
The ALTER-brain project set out to uncover how the brain’s own cells and immune system are altered by cancer, and how these changes could be turned into new opportunities for treatment and prevention. Specifically, the project aimed to:
Define how astrocytes, the most abundant brain cells, change during metastasis and how they influence cancer behavior.
Reveal how immune cells and astrocytes communicate to control or suppress anti-tumor responses.
Understand how cancer cells hijack blood vessels to survive in the brain and form large, aggressive tumors.
By addressing these questions, ALTER-brain sought to turn the complexity of the brain environment from an obstacle into a therapeutic opportunity.
The ALTER-brain project set out to uncover how the brain’s own cells and immune system are altered by cancer, and how these changes could be turned into new opportunities for treatment and prevention. Specifically, the project aimed to:
Define how astrocytes, the most abundant brain cells, change during metastasis and how they influence cancer behavior.
Reveal how immune cells and astrocytes communicate to control or suppress anti-tumor responses.
Understand how cancer cells hijack blood vessels to survive in the brain and form large, aggressive tumors.
By addressing these questions, ALTER-brain sought to turn the complexity of the brain environment from an obstacle into a therapeutic opportunity.
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.
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.
ALTER-brain went far beyond the initial state of knowledge. Before this project, astrocytes were seen mainly as passive responders to brain injury. Now, thanks to ALTER-brain, they are recognized as active regulators of immune activity, vascular adaptation, and metastatic outgrowth.
The project uncovered multiple mechanisms that can be targeted therapeutically:
TIMP1 as a mediator of local immune suppression.
CD74/MIF signaling as a druggable axis in immune rewiring.
By combining neuroscience, immunology, and cancer biology, ALTER-brain built a new conceptual bridge between brain physiology and metastasis. These findings have already inspired a new translational initiative—TheraClusters—focused on treating the tumor–stromal units that drive disease progression, which received the ERC Seal of Excellence.
The infrastructures and methods developed—such as organotypic drug screening and neural-circuit–based tumor classification—will continue to serve the scientific and medical community. Through the RENACER network, they are already being used to bring precision medicine to patients with brain metastases.
Ultimately, ALTER-brain has turned fundamental insights into practical platforms, clinical collaborations, and therapeutic opportunities. It has not only advanced our understanding of how cancer reshapes the brain, but also opened new possibilities for prevention, early intervention, and improved quality of life for patients facing this devastating disease.
The project uncovered multiple mechanisms that can be targeted therapeutically:
TIMP1 as a mediator of local immune suppression.
CD74/MIF signaling as a druggable axis in immune rewiring.
By combining neuroscience, immunology, and cancer biology, ALTER-brain built a new conceptual bridge between brain physiology and metastasis. These findings have already inspired a new translational initiative—TheraClusters—focused on treating the tumor–stromal units that drive disease progression, which received the ERC Seal of Excellence.
The infrastructures and methods developed—such as organotypic drug screening and neural-circuit–based tumor classification—will continue to serve the scientific and medical community. Through the RENACER network, they are already being used to bring precision medicine to patients with brain metastases.
Ultimately, ALTER-brain has turned fundamental insights into practical platforms, clinical collaborations, and therapeutic opportunities. It has not only advanced our understanding of how cancer reshapes the brain, but also opened new possibilities for prevention, early intervention, and improved quality of life for patients facing this devastating disease.