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.
