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Investigating the effects of arginine methylation inhibitors on microdissected brain tumour biopsies maintained in a miniaturised perfusion system
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Number of Authors: 172023 (English)In: Lab on a Chip, ISSN 1473-0197, E-ISSN 1473-0189, Vol. 23, no 11, p. 2664-2682Article in journal (Refereed) Published
Abstract [en]

Arginine methylation is a post-translational modification that consists of the transfer of one or two methyl (CH3) groups to arginine residues in proteins. Several types of arginine methylation occur, namely monomethylation, symmetric dimethylation and asymmetric dimethylation, which are catalysed by different protein arginine methyltransferases (PRMTs). Inhibitors of PRMTs have recently entered clinical trials to target several types of cancer, including gliomas (NCT04089449). People with glioblastoma (GBM), the most aggressive form of brain tumour, are among those with the poorest quality of life and likelihood of survival of anyone diagnosed with cancer. There is currently a lack of (pre)clinical research on the possible application of PRMT inhibitors to target brain tumours. Here, we set out to investigate the effects of clinically-relevant PRMT inhibitors on GBM biopsies. We present a new, low-cost, easy to fabricate perfusion device that can maintain GBM tissue in a viable condition for at least eight days post-surgical resection. The miniaturised perfusion device enables the treatment of GBM tissue with PRMT inhibitors ex vivo, and we observed a two-fold increase in apoptosis in treated samples compared to parallel control experiments. Mechanistically, we show thousands of differentially expressed genes after treatment, and changes in the type of arginine methylation of the RNA binding protein FUS that are consistent with hundreds of differential gene splicing events. This is the first time that cross-talk between different types of arginine methylation has been observed in clinical samples after treatment with PRMT inhibitors.

Place, publisher, year, edition, pages
2023. Vol. 23, no 11, p. 2664-2682
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Chemical Sciences Nano Technology Other Biological Topics Other Medical Sciences not elsewhere specified
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URN: urn:nbn:se:su:diva-230004DOI: 10.1039/d3lc00204gISI: 000988028100001PubMedID: 37191188Scopus ID: 2-s2.0-85160418171OAI: oai:DiVA.org:su-230004DiVA, id: diva2:1864509
Available from: 2024-06-03 Created: 2024-06-03 Last updated: 2024-06-03Bibliographically approved

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Iles, Alexander

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Hosni, InesIles, AlexanderScott, Ian S.Stead, Lucy F.
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