Extracellular Vesicles from Cerebrospinal Fluid of Leptomeningeal Metastasis Patients Deliver MiR-21 and Induce Methotrexate Resistance in Lung Cancer Cells

• Published in: International journal of molecular sciences Vol. 25; no. 6; p. 3124
• Main Authors: Im, Ji Hye, Lee, Kyue-Yim, Seo, Yoona, Rhim, Jiho, Dho, Yun-Sik, Yoo, Byong Chul, Park, Jong Bae, Shin, Sang Hoon, Yoo, Heon, Kim, Jong Heon, Gwak, Ho-Shin
• Format: Journal Article
• Language: English
• Published: Switzerland MDPI AG 01.03.2024; MDPI
• Subjects: Cancer; Cancer therapies; Care and treatment; Cells; Cerebrospinal fluid; Chemotherapy; Drug resistance; extracellular vesicle; Extracellular vesicles; Health aspects; leptomeningeal metastasis; Lung cancer; Lung cancer, Non-small cell; Medical prognosis; Metastasis; Methotrexate; MicroRNA; MicroRNAs; miR-21; Phosphorylation; Prognosis; Survival analysis; South Korea; methotrexate; leptomeningeal metastasis; miR-21; extracellular vesicle; cerebrospinal fluid
• ISSN: 1422-0067; 1661-6596; 1422-0067
• DOI: 10.3390/ijms25063124

Leptomeningeal metastasis (LM) is a common and fatal complication of advanced non-small cell lung cancer (NSCLC) caused by the spread of malignant cells to the leptomeninges and cerebrospinal fluid (CSF). While intra-CSF methotrexate (MTX) chemotherapy can improve prognosis, eventual MTX resistance deters continued chemotherapy. Recent studies have shown that increased miRNA-21 (miR-21) expression in the CSF of patients with LM after intraventricular MTX-chemotherapy is associated with poor overall survival; however, the molecular mechanisms underlying this resistance are poorly understood. Here, we confirm, in 36 patients with NSCLC-LM, that elevated miR-21 expression prior to treatment correlates with poor prognosis. MiR-21 overexpression or sponging results in a corresponding increase or decrease in MTX resistance, demonstrating that cellular miR-21 expression correlates with drug resistance. MiR-21-monitoring sensor and fluorescent extracellular vesicle (EV) staining revealed that EV-mediated delivery of miR-21 could modulate MTX resistance. Moreover, EVs isolated from the CSF of LM patients containing miR-21 could enhance the cell proliferation and MTX resistance of recipient cells. These results indicate that miR-21 can be transferred from cell-to-cell via EVs and potentially modulate MTX sensitivity, suggesting that miR-21 in CSF EVs may be a prognostic and therapeutic target for overcoming MTX resistance in patients with NSCLC-LM.