TY - JOUR
T1 - Inhibition of extracellular vesicle-derived miR-146a-5p decreases progression of melanoma brain metastasis via Notch pathway dysregulation in astrocytes
AU - Rigg, Emma
AU - Wang, Jiwei
AU - Xue, Zhiwei
AU - Lunavat, Taral R.
AU - Liu, Guowei
AU - Hoang, Tuyen
AU - Parajuli, Himalaya
AU - Han, Mingzhi
AU - Bjerkvig, Rolf
AU - Nazarov, Petr V.
AU - Nicot, Nathalie
AU - Kreis, Stephanie
AU - Margue, Christiane
AU - Nomigni, Miléne Tetsi
AU - Utikal, Jochen
AU - Miletic, Hrvoje
AU - Sundstrøm, Terje
AU - Ystaas, Lars A.R.
AU - Li, Xingang
AU - Thorsen, Frits
N1 - ACKNOWLEDGEMENTS
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)
© 2023 The Authors. Journal of Extracellular Vesicles published by Wiley Periodicals LLC on behalf of International Society for Extracellular Vesicles.
PY - 2023/10/1
Y1 - 2023/10/1
N2 - 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.
AB - 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.
KW - brain metastasis
KW - deserpidine
KW - extracellular vesicles
KW - melanoma
KW - miR-146a-5p
KW - normal human astrocytes (NHA)
UR - http://www.scopus.com/inward/record.url?scp=85172807861&partnerID=8YFLogxK
UR - https://pubmed.ncbi.nlm.nih.gov/37759347
U2 - 10.1002/jev2.12363
DO - 10.1002/jev2.12363
M3 - Article
C2 - 37759347
SN - 2001-3078
VL - 12
JO - Journal of Extracellular Vesicles
JF - Journal of Extracellular Vesicles
IS - 10
M1 - e12363
ER -