Vascular determinants of cancer cell fate and immune regulation in brain metastasis

Brain metastasis (BrM) is one of the deadliest cancer complications, affecting 30-40% of patients. When cancer cells migrate from the primary tumor to the brain, they face the critical challenge of adapting to an entirely new microenvironment. This includes various tissue-resident cell types, a distinct extracellular matrix composition, and more importantly, the challenge of traversing the multiple layers constituting the blood-brain barrier (BBB). The BBB – composed of the endothelial cells, mural cells, and associated microglia and neurons – not only serves as the initial gateway for cancer cells during the early stages of metastatic colonization but also for recruited immune cells, such as cytotoxic T cells, in advanced stages of the disease. The METAVASC project pioneers a novel study of the brain vasculature as a key regulator of both early and advanced stages in BrM, challenging the traditional view of the vascular system as merely structural. By following a multifaceted approach – including niche labeling systems, CRISPR and drug screenings, multiplex immunofluorescence, spatial transcriptomics, and functional studies – this project aims to overcome current limitations in understanding BrM biology from a vascular perspective, addressing two key questions: How do vascular components influence cancer cell survival during the initial stages of BrM (Aim 1)? And how does the brain vasculature regulate immune cell recruitment and activation in later stages (Aim 2)? Although immunocompetent BrM mouse models will be critical to address most of the fundamental questions in this project, the validation process in human samples represents an important milestone (Aim 3), as our ultimate goal is to translate our findings into tangible benefits for patients. In METAVASC, we aim to advance the knowledge of this disease and develop groundbreaking therapies that can transform BrM into preventable and treatable conditions, potentially revolutionizing patient outcomes.