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울산대학교 의과대학, 서울아산병원

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Research, 10 Feb 2026 | https://doi.org/10.34133/research.1126 Tumor Exosomal L1 Cell Adhesion Molecule Promotes Brain Metastasis of Lung Cancer

Dong Ha Kim¹, Chae Won Lee¹, Yun Jung Choi¹, Da-Som Kim², Kyosun Ban², Juhyeon Hong², Gyeong Joon Moon³, Sang-Yeob Kim⁴, Chan-Gi Pack⁴, In-Jeoung Baek⁵, Jin-Yong Jeong⁴, Dong-Cheol Woo⁶, Ji-Hye Oh⁷, Chang Ohk Sung⁷, Kyunggon Kim⁸, Hyun-Yi Kim⁹, Hae-Yun Jung¹⁰, Wonjun Ji¹¹, Min Jee Kim¹¹, Chang Min Choi¹¹, Jae Cheol Lee^12*, and Jin Kyung Rho^2,4*

¹Asan Institute for Life Sciences, Asan Medical Center, University of Ulsan College of Medicine, Seoul,South Korea.
²Department of Biochemistry and Molecular Biology, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
³Center for Cell Therapy, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁴Department of Convergence Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁵Departmentof Cell and Genetic Engineering, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁶MR/CT/US Core Laboratory, Asan Medical Institute of Convergence and Technology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁷Bioinformatics CoreLaboratory, Convergence Medicine Research Center, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁸Department of Digital Medicine, Brain Korea 21 Project, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
⁹NGeneS Inc., Asna-Si, Gyeonggi-do, South Korea.
¹⁰Division of Radiation Biomedical Research, Korea Institute of Radiological and Medical Sciences, Seoul, South Korea.
¹¹Department of Pulmonary and Critical Care Medicine, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea.
¹²Department of Oncology, Asan Medical Center, University of Ulsan College of Medicine, Seoul, South Korea

^*Address correspondence to: J.C.L.; J.K.R.

Abstract

Brain metastasis (BrM) is a common occurrence in lung cancer and substantially worsens the prognosis due to the blood-brain barrier (BBB), which restricts drug entry into the brain. Here, we found that exosomes secreted by lung cancer cells that had acquired epidermal growth factor receptor tyrosine kinase inhibitor resistance and undergone epithelial-mesenchymal transition (osimertinib- and WZ4002-resistant H1975) exhibited enhanced brain-specific distribution and a concomitant increase in BrM compared with exosomes from parental H1975 cells. To identify exosomal mediators of this phenotype, liquid chromatography-tandem mass spectrometry-based proteomic analysis was performed. Exosomes derived from resistant cell lines exhibited distinct protein profiles relative to parental cells, with 744 exosomal proteins significantly altered (fold change ≥ 2; P ≤ 0.05). Prioritization of membrane proteins and ligand-receptor interaction analysis identified ITGAV (integrin αV), ITGB3 (intergrin β3), and L1CAM (L1 cell adhesion molecule) as candidates interacting with brain-specific ligands, including neural cell adhesion molecule 1 (NCAM1) and contactin 2. Validation of exosomal association by Western blotting identified ITGB3 and L1CAM as final candidates. Subsequent functional modulation studies demonstrated that exosomal L1CAM plays a dominant role in brain distribution and metastatic progression. Exosomal L1CAM increased BBB permeability by disrupting endothelial tight-junction integrity both in vitro and in vivo. This effect was associated with the involvement of NCAM1 on BBB endothelial cells, as suggested by an exosomal L1CAM masking experiment. Clinically, exosomal L1CAM demonstrated diagnostic potential for BrM (area under the curve [AUC] = 0.80), and a combined exosomal L1CAM/ITGB3 panel significantly improved diagnostic accuracy (AUC = 0.98). Collectively, these findings identify exosomal L1CAM as a key regulator of brain-specific metastasis and support the clinical utility of the L1CAM/ITGB3 panel as a noninvasive biomarker for BrM in lung cancer.

논문소개전체 설명

폐암은 주로 뇌, 간, 뼈, 부신 등으로 전이가 이루어지는데, 이러한 현상이 랜덤하게 이루어지지 않고 암세포 분비 엑소좀을 통해서 발생할 수 있는 가능성을 확인함. 본 논문에서는 특정 엑소좀의 바이오마커가 뇌 쪽으로 이동을 촉진시키고 BBB permeability를 증가시켜 뇌 전이 환경을 촉진시킬 수 있음을 확인하였고 이러한 바이오마커로 L1CAM 단백질을 제시하였음. 임상적 의미로는 엑소좀 L1CAM/ITGB3 panel이 뇌전이 예측 바이오마커의 가능성을 검증함.

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