Periodic Reporting for period 4 - 3DBrainStrom (Brain metastases: Deciphering tumor-stroma interactions in three dimensions for the rational design of nanomedicines)
Reporting period: 2023-10-01 to 2025-03-31
Summary of the Context and Overall Objectives of the Project
Scientific context and problem addressed:
Brain metastases (BM) represent one of the most devastating complications of systemic cancer, affecting patients with melanoma, breast, and lung cancers. Despite major advances in systemic therapy, brain metastases remain largely incurable due to the unique biological and physiological barriers of the brain, such as the blood-brain barrier (BBB), immune privilege, and tumor-microenvironment interactions. Conventional two-dimensional (2D) cell cultures fail to capture these complexities, creating a major translational gap between laboratory findings and clinical outcomes.
Importance for society:
Brain metastases are increasingly common as patient survival improves with better systemic therapies. They severely impact quality of life and survival, posing a major clinical challenge. Understanding the mechanisms that allow tumor cells to colonize and adapt to the brain is crucial for developing targeted and effective therapies. The project aimed to improve the ability to predict therapeutic response and enable precision treatment of patients with metastatic disease to the brain.
Overall objectives:
The ERC Advanced Grant 3DBrainStrom project set out to:
1. Develop physiologically relevant 3D preclinical models that recapitulate the brain metastatic niche for melanoma, breast, and lung cancers.
2. Identify molecular drivers and biomarkers underlying metastatic colonization and immune evasion in the brain.
3. Design and validate nanomedicine platforms that can cross the BBB, target tumor and stromal components, and deliver therapeutic agents effectively to metastatic brain lesions.
4. Translate these discoveries into clinically applicable precision nanomedicine strategies and lay the foundation for patient-specific therapy prediction.
The project’s conclusions demonstrate that these goals were successfully achieved, bridging fundamental cancer biology with translational nanomedicine.
Scientific context and problem addressed:
Brain metastases (BM) represent one of the most devastating complications of systemic cancer, affecting patients with melanoma, breast, and lung cancers. Despite major advances in systemic therapy, brain metastases remain largely incurable due to the unique biological and physiological barriers of the brain, such as the blood-brain barrier (BBB), immune privilege, and tumor-microenvironment interactions. Conventional two-dimensional (2D) cell cultures fail to capture these complexities, creating a major translational gap between laboratory findings and clinical outcomes.
Importance for society:
Brain metastases are increasingly common as patient survival improves with better systemic therapies. They severely impact quality of life and survival, posing a major clinical challenge. Understanding the mechanisms that allow tumor cells to colonize and adapt to the brain is crucial for developing targeted and effective therapies. The project aimed to improve the ability to predict therapeutic response and enable precision treatment of patients with metastatic disease to the brain.
Overall objectives:
The ERC Advanced Grant 3DBrainStrom project set out to:
1. Develop physiologically relevant 3D preclinical models that recapitulate the brain metastatic niche for melanoma, breast, and lung cancers.
2. Identify molecular drivers and biomarkers underlying metastatic colonization and immune evasion in the brain.
3. Design and validate nanomedicine platforms that can cross the BBB, target tumor and stromal components, and deliver therapeutic agents effectively to metastatic brain lesions.
4. Translate these discoveries into clinically applicable precision nanomedicine strategies and lay the foundation for patient-specific therapy prediction.
The project’s conclusions demonstrate that these goals were successfully achieved, bridging fundamental cancer biology with translational nanomedicine.
Research and technological achievements:
From the project’s start, our team established a comprehensive suite of 3D experimental models mimicking the human brain microenvironment. These included 3D-bioprinted primary (glioblastoma) and secondary (melanoma, breast, and lung cancer metastases) brain cancer constructs, tumoroids, and tumor-on-a-chip microfluidic systems that accurately replicated the physiological, cellular, and mechanical features of brain metastases. These platforms enabled dynamic analyses of tumor-vascular, glial, and immune interactions, drug penetration, and resistance.
Through integrated transcriptomic and functional studies, our group identified major molecular mediators of brain metastasis. For example:
1. In breast cancer brain metastases, loss of p53 induced lipid metabolic reprogramming via SCD1, while its inhibition prevented metastatic outgrowth.
2. In melanoma brain metastases, the CCL2/CCR2 axis emerged as a key driver of immune suppression; its blockade reduced metastatic burden.
3. In breast cancer brain metastases of BRCA1-deficient tumors, treatment with PARP inhibitors induced PD-L1 expression, revealing an adaptive immune escape mechanism; dual inhibition of these synthetically lethal targets co-delivered by a targeted nanoparticle overcame the acquired immunosuppression.
4. P-selectin was identified as a radiation-inducible vascular target, enabling selective nanoparticle delivery to irradiated brain metastases.
Nanomedicine development:
Based on these insights, several precision nanomedicine systems were engineered, including:
1. Dual-drug nanoparticles co-delivering BRAF and MEK inhibitors, overcoming drug resistance in BRAF-mutant primary melanoma and its brain metastases.
2. Theranostic nanoparticles for simultaneous intraoperative imaging and post-surgical therapy.
3. Radiation-guided nanoparticles that exploit radiation-induced endothelial P-selectin expression for targeted dual-drug delivery of PARP inhibitor and small-molecule PD-L1 inhibitor.
All formulations were fully characterized (size, charge, loading, release, targeting, biodistribution) and validated in vivo in murine models. These systems provided proof of concept for translational precision nanomedicine capable of treating brain metastases with high specificity and reduced toxicity.
Dissemination and exploitation:
The project’s results were published in high-impact journals such as Nature Communications, Science Advances, Nature Genetics, Nature Reviews Cancer, Nature Reviews Bioengineering, Brain, and Journal of Controlled Release, and presented in numerous international conferences (AACR, CRS, EACR, GRC, Keystone). The research fostered collaborations between chemists, biologists, clinicians, and engineers, and supported training for young scientists who successfully defended their PhDs. The methodologies have already influenced a clinical trial involving 80 patients, designed to validate 3D cancer models for personalized therapy prediction.
Societal impact:
This work provided new mechanistic understanding of how tumors adapt to the brain and yielded practical preclinical tools for evaluating therapies in a human-relevant context. The project’s results move cancer treatment closer to the vision of transforming brain metastases from fatal to manageable chronic conditions.
From the project’s start, our team established a comprehensive suite of 3D experimental models mimicking the human brain microenvironment. These included 3D-bioprinted primary (glioblastoma) and secondary (melanoma, breast, and lung cancer metastases) brain cancer constructs, tumoroids, and tumor-on-a-chip microfluidic systems that accurately replicated the physiological, cellular, and mechanical features of brain metastases. These platforms enabled dynamic analyses of tumor-vascular, glial, and immune interactions, drug penetration, and resistance.
Through integrated transcriptomic and functional studies, our group identified major molecular mediators of brain metastasis. For example:
1. In breast cancer brain metastases, loss of p53 induced lipid metabolic reprogramming via SCD1, while its inhibition prevented metastatic outgrowth.
2. In melanoma brain metastases, the CCL2/CCR2 axis emerged as a key driver of immune suppression; its blockade reduced metastatic burden.
3. In breast cancer brain metastases of BRCA1-deficient tumors, treatment with PARP inhibitors induced PD-L1 expression, revealing an adaptive immune escape mechanism; dual inhibition of these synthetically lethal targets co-delivered by a targeted nanoparticle overcame the acquired immunosuppression.
4. P-selectin was identified as a radiation-inducible vascular target, enabling selective nanoparticle delivery to irradiated brain metastases.
Nanomedicine development:
Based on these insights, several precision nanomedicine systems were engineered, including:
1. Dual-drug nanoparticles co-delivering BRAF and MEK inhibitors, overcoming drug resistance in BRAF-mutant primary melanoma and its brain metastases.
2. Theranostic nanoparticles for simultaneous intraoperative imaging and post-surgical therapy.
3. Radiation-guided nanoparticles that exploit radiation-induced endothelial P-selectin expression for targeted dual-drug delivery of PARP inhibitor and small-molecule PD-L1 inhibitor.
All formulations were fully characterized (size, charge, loading, release, targeting, biodistribution) and validated in vivo in murine models. These systems provided proof of concept for translational precision nanomedicine capable of treating brain metastases with high specificity and reduced toxicity.
Dissemination and exploitation:
The project’s results were published in high-impact journals such as Nature Communications, Science Advances, Nature Genetics, Nature Reviews Cancer, Nature Reviews Bioengineering, Brain, and Journal of Controlled Release, and presented in numerous international conferences (AACR, CRS, EACR, GRC, Keystone). The research fostered collaborations between chemists, biologists, clinicians, and engineers, and supported training for young scientists who successfully defended their PhDs. The methodologies have already influenced a clinical trial involving 80 patients, designed to validate 3D cancer models for personalized therapy prediction.
Societal impact:
This work provided new mechanistic understanding of how tumors adapt to the brain and yielded practical preclinical tools for evaluating therapies in a human-relevant context. The project’s results move cancer treatment closer to the vision of transforming brain metastases from fatal to manageable chronic conditions.
The project advanced the field significantly beyond the existing state of the art in three main areas:
1. Modeling complexity: The creation of 3D-bioprinted and microfluidic systems that replicate tumor-brain interactions established a new experimental standard, bridging the gap between in vitro and in vivo research.
2. Mechanistic discovery: Integration of multi-omic analyses with functional studies identified novel molecular pathways, such as p53-SCD1 and CCL2/CCR2, that govern brain metastasis and immune evasion, opening therapeutic opportunities.
3. Translational nanomedicine: The development of modular, dual-drug, and image-guided nanoplatforms capable of crossing the BBB represents a paradigm shift in targeted therapy to the brain.
Building on these advances, our research group will further develop patient-informed 3D models, refine nanomedicine formulations for clinical translation, and extend collaborations with hospitals and industry partners. The technologies and knowledge generated are expected to accelerate personalized therapeutic strategies for patients with brain metastases and other hard-to-treat cancers.
1. Modeling complexity: The creation of 3D-bioprinted and microfluidic systems that replicate tumor-brain interactions established a new experimental standard, bridging the gap between in vitro and in vivo research.
2. Mechanistic discovery: Integration of multi-omic analyses with functional studies identified novel molecular pathways, such as p53-SCD1 and CCL2/CCR2, that govern brain metastasis and immune evasion, opening therapeutic opportunities.
3. Translational nanomedicine: The development of modular, dual-drug, and image-guided nanoplatforms capable of crossing the BBB represents a paradigm shift in targeted therapy to the brain.
Building on these advances, our research group will further develop patient-informed 3D models, refine nanomedicine formulations for clinical translation, and extend collaborations with hospitals and industry partners. The technologies and knowledge generated are expected to accelerate personalized therapeutic strategies for patients with brain metastases and other hard-to-treat cancers.