RBM10 Deficiency Promotes Brain Metastasis by Modulating Sphingolipid Metabolism in a BBB Model of EGFR Mutant Lung Adenocarcinoma

Overview

Journal J Exp Clin Cancer Res

Publisher Biomed Central

Specialty Oncology

Date 2025 Mar 12

PMID 40069781

Authors

Gang Xu

Bo An

Ruqiong Wang

Bo Pan

Huiting Hao

Xingmei Ren

Zihan Jing

Weitong Gao

Yajie Li

Yan Jin

Enguang Lin

Lihua Shang

Dexin Jia

Yan Yu

Affiliations

Soon will be listed here.

Abstract

Background: Brain metastasis significantly contributes to the failure of targeted therapy in patients with epidermal growth factor receptor (EGFR)-mutated lung adenocarcinoma (LUAD). Reduced expression of RNA-binding motif protein 10 (RBM10) is associated with brain metastasis in these patients. However, the mechanism by which RBM10 affects brain metastasis in EGFR-mutated LUAD remains unclear.

Methods: An in vitro blood-brain barrier (BBB) model and brain metastasis-prone cell lines (BrM3) were established to confirm the brain metastatic potential of tumor cells following RBM10 knockdown. The roles of RBM10 and galactosylceramidase (GALC) in LUAD brain metastases were analyzed using cellular phenotypic assays and molecular biology techniques, including the combined analysis of Nanopore sequencing and CLIP-seq, minigene assays, and others.

Results: 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, 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 BBB permeability, thereby promoting brain metastasis. Additionally, animal experiments show that the targeted agents Fingolimod (an S1P inhibitor) and RU-SKI-43 (a potential drug for RBM10 mutation) suppress the growth of brain metastasis.

Conclusion: This study offers insights into the potential mechanisms of brain metastasis in LUAD and suggests a possible therapeutic target for further investigation.

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