Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes.
Rigg, Emma; Wang, Jiwei; Xue, Zhiweiet al.
2023 • In Journal of Extracellular Vesicles, 12 (10), p. 12363
[en] Melanoma has the highest propensity of all cancers to metastasize to the brain with a large percentage of late-stage patients developing metastases in the central nervous system (CNS). It is well known that metastasis establishment, cell survival, and progression are affected by tumour-host cell interactions where changes in the host cellular compartments likely play an important role. In this context, miRNAs transferred by tumour derived extracellular vesicles (EVs) have previously been shown to create a favourable tumour microenvironment. Here, we show that miR-146a-5p is highly expressed in human melanoma brain metastasis (MBM) EVs, both in MBM cell lines as well as in biopsies, thereby modulating the brain metastatic niche. Mechanistically, miR-146a-5p was transferred to astrocytes via EV delivery and inhibited NUMB in the Notch signalling pathway. This resulted in activation of tumour-promoting cytokines (IL-6, IL-8, MCP-1 and CXCL1). Brain metastases were significantly reduced following miR-146a-5p knockdown. Corroborating these findings, miR-146a-5p inhibition led to a reduction of IL-6, IL-8, MCP-1 and CXCL1 in astrocytes. Following molecular docking analysis, deserpidine was identified as a functional miR-146a-5p inhibitor, both in vitro and in vivo. Our results highlight the pro-metastatic function of miR-146a-5p in EVs and identifies deserpidine for targeted adjuvant treatment.
Disciplines :
Oncologie
Auteur, co-auteur :
Rigg, Emma ; Department of Biomedicine, University of Bergen, Bergen, Norway
Wang, Jiwei; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China ; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Xue, Zhiwei; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Lunavat, Taral R; Department of Biomedicine, University of Bergen, Bergen, Norway ; Department of Neurology, Molecular Neurogenetics Unit-West, Massachusetts General Hospital, Harvard Medical School, Charlestown, Massachusetts, USA
Liu, Guowei; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Hoang, Tuyen; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China
Parajuli, Himalaya ; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China
Han, Mingzhi; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China ; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Bjerkvig, Rolf; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China
Nazarov, Petr V; Bioinformatics Platform and Multiomics Data Science Research Group, Department of Cancer Research, Luxembourg Institute of Health, Luxembourg
Nicot, Nathalie; LuxGen Genome Center, Luxembourg Institute of Health, Laboratoire National de Santé, Dudelange, Luxembourg
KREIS, Stephanie ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
WURTH-MARGUE, Christiane ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
TETSI NOMIGNI, Milène ; University of Luxembourg > Faculty of Science, Technology and Medicine (FSTM) > Department of Life Sciences and Medicine (DLSM)
Utikal, Jochen; Skin Cancer Unit, German Cancer Research Center (DKFZ), Heidelberg, Germany ; Department of Dermatology, Venereology and Allergology, University Medical Center Mannheim, Ruprecht-Karl University of Heidelberg, Mannheim, Germany ; DKFZ Hector Cancer Institute at the University Medical Center Mannheim, Mannheim, Germany
Miletic, Hrvoje; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China ; Department of Pathology, Haukeland University Hospital, Bergen, Norway
Sundstrøm, Terje; Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway ; Department of Clinical Medicine, University of Bergen, Bergen, Norway
Ystaas, Lars A R; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China
Li, Xingang; Department of Biomedicine, University of Bergen, Bergen, Norway ; Shandong Key Laboratory of Brain Function Remodeling, Jinan, China
Thorsen, Frits; Department of Neurosurgery, Qilu Hospital of Shandong University and Institute of Brain and Brain-Inspired Science, Cheeloo College of Medicine, Shandong University, Jinan, China ; Department of Biomedicine, University of Bergen, Bergen, Norway ; Department of Neurosurgery, Haukeland University Hospital, Bergen, Norway ; Molecular Imaging Center, Department of Biomedicine, University of Bergen, Bergen, Norway
Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes.
National Natural Science Foundation of China Helse Vest Universitetet i Bergen Norges Forskningsråd Kreftforeningen
Subventionnement (détails) :
The TEM, confocal and MR imaging was performed at The Molecular Imaging Centre, Department of Biomedicine, University of Bergen, Norway. Technical assistance from Aurea Castilho, Department of Biomedicine, University of Bergen, is highly appreciated. This work was supported by the Norwegian Cancer Society (182716), The Western Norway Regional Health Authority (F‐12856‐D11661), The Norwegian Research Council (315566), the University of Bergen, The National Natural Science Foundation of China (82073219, 82203760), the Department of Science & Technology of Shandong Province (ZR2020QH182), and Luxembourg National Research Fund (C21/BM/15739125/DIOMEDES).
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