Neuro-mimetic reprogramming and epigenetic unlocking drive lung cancer stem cell adaptation to the brain microenvironment

Brain metastasis represents a lethal complication of non-small cell lung cancer, driven by the ability of disseminated tumor cells to colonize the central nervous system microenvironment. Although cancer stem cells (CSCs) are recognized as key drivers of metastatic initiation, whether their contact with the brain parenchyma induces terminal differentiation or adaptive plasticity remains controversial. Here, using an in vivo model of lung-derived CSCs injected intracranially, combined with quantitative total proteomics and phosphoproteomics, we demonstrate that contact with the brain niche triggers a neuro-mimetic reprogramming rather than terminal differentiation. Lung CSCs desensitize their systemic metastatic program while epigenetically unlocking neural stem cell networks, characterized by the upregulation of Ngfr, Fabp7, Pbx3, Vgf, and S100b, concurrent with the downregulation of the DNA methyltransferase Dnmt3a and the cytosolic exclusion of Id1. Phosphoproteomic profiling revealed post-translational adaptations, highlighted by hyperphosphorylation of Nestin at S957 and S963. Furthermore, kinase substrate enrichment analysis uncovered high activity of Prkcq (PKCθ) and Map3k7 (TAK1), shifting the cellular state toward structural remodelling and microenvironmental stress tolerance. Functional validation assays using selective inhibitors confirmed that these kinase networks represent adaptive liabilities within tissue constraints rather than basic in vitro survival requirements. Together, our findings demonstrate that lung CSCs exploit a phenotypic plasticity to adapt to the brain niche, acquiring a neural-glial disguise that supports vascular co-option, immune evasion, and metastatic colonization.