Abstract Brain metastasis represents one of the most devastating complications of lung adenocarcinoma (LUAD) and remains a major cause of cancer-related mortality. The metastatic spread of LUAD to the brain is not a random event but a highly coordinated, multistep process that requires tumor cells to dynamically adapt to changing microenvironments. Epithelial-mesenchymal transition (EMT) has emerged as a central driver of this phenotypic plasticity. Rather than functioning as a simple binary switch, EMT encompasses a spectrum of reversible cellular states that endow tumor cells with enhanced motility, survival in circulation, and the capacity to cross the blood-brain barrier, followed by re-acquisition of epithelial traits that support metastatic colonization. In this review, we discuss how EMT-associated plasticity shapes each stage of LUAD brain metastasis, from local invasion and systemic dissemination to intracranial adaptation and outgrowth. We further examine the regulatory networks that integrate microenvironmental cues with transcriptional and epigenetic programs to sustain these dynamic state transitions. Finally, we highlight the clinical implications of EMT-driven heterogeneity, including its impact on therapeutic resistance and disease progression, and outline emerging strategies aimed at targeting metastatic plasticity. A deeper understanding of EMT as a context-dependent and reversible process may open new avenues for the prevention and treatment of LUAD brain metastasis.
Feng et al. (Tue,) studied this question.
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