Xu Gang, An Bo, Wang Ruqiong, Pan Bo, Hao Huiting, Ren Xingmei, Jing Zihan, Gao Weitong, Li Yajie, Jin Yan, Lin Enguang, Shang Lihua, Jia Dexin, Yu Yan
Department of Medical Oncology, Harbin Medical University Cancer Hospital, Harbin, 150040, China.
Department of Clinical Laboratory, Harbin Medical University Cancer Hospital, Harbin, 150040, China.
J Exp Clin Cancer Res. 2025 Mar 11;44(1):95. doi: 10.1186/s13046-025-03347-1.
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.
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.
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.
This study offers insights into the potential mechanisms of brain metastasis in LUAD and suggests a possible therapeutic target for further investigation.
脑转移显著导致表皮生长因子受体（EGFR）突变的肺腺癌（LUAD）患者靶向治疗失败。RNA结合基序蛋白10（RBM10）表达降低与这些患者的脑转移相关。然而，RBM10影响EGFR突变型LUAD脑转移的机制仍不清楚。
建立体外血脑屏障（BBB）模型和易发生脑转移的细胞系（BrM3），以确认RBM10敲低后肿瘤细胞的脑转移潜能。使用细胞表型分析和分子生物学技术，包括纳米孔测序和CLIP-seq的联合分析、小基因分析等，分析RBM10和半乳糖神经酰胺酶（GALC）在LUAD脑转移中的作用。
本研究表明，RBM10通过调节鞘脂代谢在抑制EGFR突变型LUAD的脑转移中起重要作用。当RBM1o表达较低时，GALC进入细胞核发挥作用。RBM10缺乏抑制GALC剪接过程中的外显子跳跃，导致GALC表达上调和鞘氨醇1-磷酸（S1P）合成增加。S1P增强血脑屏障通透性，从而促进脑转移。此外，动物实验表明，靶向药物芬戈莫德（一种S1P抑制剂）和RU-SKI-43（一种针对RBM10突变的潜在药物）可抑制脑转移瘤的生长。
本研究为LUAD脑转移的潜在机制提供了见解，并提出了一个可能的治疗靶点以供进一步研究。
