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

Abstract

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.