Cerebral vasculature shapes the spatial patterning of brain metastases

PACM-03 TUMOR–BRAIN CROSSTALK DRIVES NEURAL MICROENVIRONMENT REMODELING AND PROMOTE DEMYELINATION IN BRAIN METASTASES

Abstract Brain metastases(BM) represent the most common intracranial tumors and are associated with a markedly worse prognosis compared with metastases at other sites. Metastatic lesions that colonize the brain adapt to its unique cellular and metabolic microenvironment. This adaptation drives the emergence of specialized tumor subpopulations with altered biological behavior. Understanding how metastatic tumors interact with and influence the surrounding neural tissue is therefore essential for developing strategies that preserve neurological function. The objective of this study was to investigate the interactions between BM and the surrounding brain parenchyma, with particular emphasis on the mechanisms underlying demyelination and neuronal impairment. Brain metastasis organoids(BMOs) were generated from surgically resected patient BM specimens and co-cultured with long-term viable human brain slices. Immunofluorescence staining was used to evaluate changes in myelination and cellular responses within the brain tissue. In parallel, transcriptomic profiling and tumor–brain parenchymal ligand–receptor interaction analyses were performed to identify dysregulated molecular signaling pathways with potential therapeutic relevance. BMOs successfully integrated with human brain slices and reproduced key characteristics of tumor behavior within the neural microenvironment. Myelin basic protein(MBP) immunostaining demonstrated significant demyelination in brain slices co-cultured with BMOs compared with control slices(P < 0.05). Transcriptomic analysis revealed clusters of differentially expressed genes, including marked downregulation of pathways associated with myelination and neurogenesis. Further investigation identified critical regulators of neuronal and glial function, including a downregulated gene network involved in myelin maintenance. Ligand–receptor interaction analysis revealed prominent dysregulation of NGF and TGF-β signaling. Pharmacologic targeting of these pathways in co-culture experiments significantly restored MBP signal intensity(P < 0.05). These findings demonstrate that BM actively disrupt myelin homeostasis and neural signaling within surrounding brain tissue. This ex-vivo platform provides a robust experimental system to study tumor–brain interactions and to evaluate therapeutic strategies aimed at limiting tumor-induced neurological damage.

76 Metabolic Heterogeneity in Brain Tumours: Distinguishing Brain Metastases from Glioblastomas

Brain metastases account for nearly 20% of cancer-related deaths and have a five-year survival rate of 2.4%, most commonly arising from breast and lung cancers. Despite therapeutic advances, prognosis remains poor, highlighting the need for novel treatment strategies. Metabolic reprogramming is a hallmark of cancer, reflecting the ability of malignant cells to remodel metabolic pathways to support invasion, proliferation, and survival. The brain microenvironment is metabolically distinct, characterized by restricted nutrient availability, high neuronal activity, and a tightly regulated blood-brain barrier. Tumour cells metastasizing from extracranial sites must therefore undergo metabolic adaptation to colonize and proliferate within the brain. This study investigates metabolic differences between brain metastases and primary brain tumours to identify adaptive metabolic pathways with therapeutic potential. Steady-state metabolic profiling was performed on fresh-frozen tumour tissues from patients undergoing surgical resection for glioblastoma(GBM), breast and lung cancer brain metastases at Queen Elizabeth Hospital, Birmingham. Findings were validated in patient-derived 2D cell models and ex vivo tumour slices using 13C6-glucose and 13C6-palmitate isotope tracing to assess pathway utilisation. Polar metabolites were analysed using LC-MS, and non-polar metabolites using GC-MS. Breast cancer brain metastases exhibited elevated free fatty acids relative to GBM, indicating increased de-novo lipogenesis to support membrane biosynthesis, energy production, and tumour growth within lipid-restricted brain environment. This was supported by increased FASN and ACC1 expression and PLIN2 staining for lipid droplets. In contrast, lung cancer brain metastases showed elevated GABA and glutamine levels, suggesting metabolic adaptation through neuronal/glial pathways and utilisation of neurotransmitter-linked substrates. Brain metastases exhibit tumour-type specific metabolic reprogramming to adapt to the brain microenvironment highlighting distinct metabolic survival strategies compared to GBM, and supporting the need for tumour-specific treatment strategies.

Spatial atlas of the human brain vasculature reveals specialized cell ensembles.

A comprehensive cerebrovascular cell atlas encompassing 314,535 transcriptomes is constructed that captures the arteriovenous axis and defines consensus cell states and identifies ensemble-specific susceptibilities and candidate therapeutic targets across neurological diseases, including small vessel disease and stroke.

Neural–Tumor and Microenvironmental Interactions in Brain Metastases from Lung Cancer: From Blood–Brain Barrier Traversal to Adaptation within the Brain

Brain metastases from lung cancer do not merely reflect passive tumor growth after entry into the central nervous system. Rather, their development is a dynamic process involving transvascular entry into the brain, remodeling of the intracranial microenvironment, metabolic adaptation, and changes in neural function. Advances in single-cell and spatial omics, electrophysiology, and functional models have increasingly clarified the interactions between lung cancer cells and host cells in the brain. Current evidence indicates that brain metastasis is associated with the selection of specific malignant cell states and is shaped by the brain vascular endothelium and blood–brain barrier integrity. Once within the brain, astrocytes, microglia, oligodendrocytes, and adaptive immune cells collectively shape the metastatic niche through signaling, metabolic exchange, and spatial organization. Local nutrient availability and metabolites such as lactate, cholesterol, and other lipids further influence tumor cell survival and growth. Neural adaptation differs markedly across lung cancer subtypes. In small-cell lung cancer (SCLC), more direct evidence supports intrinsic electrical excitability and functional neuron–tumor interactions, whereas evidence in non-small-cell lung cancer (NSCLC) remains centered on neural-like transcriptional states and neurotransmitter-related signaling; whether comparable functional neural connections are a general feature of NSCLC remains unclear. Overall, lung cancer brain metastasis is best viewed as a multilayered adaptive process involving tumor cell states, the brain vasculature, glial and immune microenvironments, metabolism, and neural signaling. Future studies should define the temporal and causal relationships among these mechanisms and establish their generalizability and translational relevance across lung cancer subtypes and patient populations.

Spatial distribution and prognostic significance of hemorrhagic imaging features in brain metastases from metastatic renal cell carcinoma

The Tumor Microenvironment in Non-Small Cell Lung Cancer Brain Metastases: Composition, Dynamics, and Therapeutic Implications

Brain metastases (BM) are a common and clinically significant complication of non-small cell lung cancer (NSCLC), representing a major contributor to its high mortality. Among all metastatic sites, involvement of the central nervous system (CNS) is associated with a particularly profound deterioration in patients' quality of life. The incidence of BM varies considerably across different histological subtypes and molecularly defined groups of NSCLC. The development of BM is a multistep process involving primary tumor invasion, hematogenous dissemination, blood-brain barrier (BBB) transmigration, and successful colonization of the brain. This process is strongly shaped by reciprocal interactions between the tumor cells and the unique brain tumor microenvironment (TME). Brain endothelial cells, pericytes, astrocytes, microglia, neurons, and recruited peripheral immune and stromal cells collectively regulate BBB permeability, immune evasion, extracellular matrix remodeling, and metastatic outgrowth. Compared with primary lung tumors, BM displays a distinct immune landscape characterized by reduced lymphocyte infiltration, enrichment of immunosuppressive myeloid populations, impaired antigen presentation, and extensive crosstalk with CNS-resident cells. These features contribute to therapeutic resistance and help explain the heterogeneous intracranial efficacy of systemic treatments. While immune checkpoint inhibitors and chemotherapy combinations provide benefit in selected patients, the most pronounced intracranial responses are observed with CNS-penetrant targeted therapies in molecularly defined subsets. Emerging strategies aim to directly target the metastatic niche, including myeloid cells, tumor vasculature, immune checkpoints, and cellular immunotherapies. A deeper understanding of the brain metastatic ecosystem may enable the development of more effective, biology-driven therapeutic approaches for NSCLC BM.