RBM10 Deficiency Promotes Brain Metastasis by Modulating Sphingolipid Metabolism in an Animal Model of EGFR Mutation Lung Adenocarcinoma

Brain metastasis significantly contributes to the failure of targeted therapy in patients with EGFR-mutated lung adenocarcinoma (LUAD). Reduced expression of RBM10 is associated with brain metastasis in these patients. However, the mechanism by which RBM10 affects brain metastasis in EGFR-mutated LUAD remains unclear. Previous studies reveal that RBM10 mutations lead to decreased expression and deregulated splicing at a subset of junctions, primarily through exon skipping. Overall design: This study demonstrates that RBM10 plays a vital role in inhibiting brain metastasis from EGFR-mutated LUAD by modulating sphingolipid metabolism. When RBM10 expression is low, galactosylceramidase (GALC) enters the nucleus to function. RBM10 deficiency inhibits exon skipping during GALC splicing, leading to upregulated GALC expression and increased sphingosine 1-phosphate (S1P) synthesis. S1P enhances blood-brain barrier (BBB) permeability, thereby promoting brain metastasis. Additionally, animal experiments show that the targeted agents Fingolimod (an S1P inhibitor) and RU-SKI-43 (an RBM10 inhibitor) suppress the growth of brain metastasis. This study provides a novel theoretical foundation for preventing brain metastasis in LUAD and identifies a promising therapeutic target.