ABCB1 inhibition provides a novel therapeutic target to block TWIST1-induced migration in medulloblastoma

Nasir, Aishah; Cardall, Alice; Othman, Ramadhan T; Nicolaou, Niovi; Lourdusamy, Anbarasu; Linke, Franziska; Onion, David; Ryzhova, Marina; Cameron, Hanna; Valente, Cara; Korshunov, Andrey; Pfister, Stefan M; Grabowska, Anna M; Kerr, Ian D; Coyle, Beth

Abstract

Background: Therapeutic intervention in metastatic medulloblastoma is dependent upon elucidating the underlying metastatic mechanism. We investigated whether an epithelialmesenchymal transition (EMT)-like pathway could drive medulloblastoma metastasis.
Methods: A 3D Basement Membrane Extract (3D-BME)-model was used to investigate medulloblastoma cell migration. Cell line growth was quantified with AlamarBlue metabolic assays and morphology assessed by time-lapse imaging. Gene expression was analysed by qRT-PCR and protein expression by immunohistochemistry of patient tissue microarrays and mouse orthotopic xenografts. Chromatin immunoprecipitation was used to determine whether the EMT transcription factor TWIST1 bound to the promoter of the multidrug pump ABCB1. TWIST1 was overexpressed in MED6 cells by lentiviral transduction (MED6-TWIST1). Inhibition of ABCB1 was mediated by vardenafil and TWIST1 expression was reduced by either Harmine or shRNA.
Results: Metastatic cells migrated to form large metabolically active aggregates, whereas nontumorigenic/ non-metastatic cells formed small aggregates with decreasing metabolic activity. TWIST1 expression was upregulated in the 3D-BME model. TWIST1 and ABCB1 were significantly associated with metastasis in patients (p=0.041 and p=0.04 respectively). High nuclear TWIST1 expression was observed in the invasive edge of the MED1 orthotopic model, and TWIST1 knock-down in cell lines was associated with reduced cell migration (p

Citation

Nasir, A., Cardall, A., Othman, R. T., Nicolaou, N., Lourdusamy, A., Linke, F., …Coyle, B. (2021). ABCB1 inhibition provides a novel therapeutic target to block TWIST1-induced migration in medulloblastoma. Neuro-Oncology Advances, 3(1), https://doi.org/10.1093/noajnl/vdab030

• Journal Article Type: Article
• Acceptance Date: Feb 9, 2021
• Online Publication Date: Apr 28, 2021
• Publication Date: Jan 1, 2021
• Deposit Date: Feb 12, 2021
• Publicly Available Date: Feb 12, 2021
• Journal: Neuro-Oncology Advances
• Publisher: Oxford University Press (OUP)
• Peer Reviewed: Peer Reviewed
• Volume: 3
• Issue: 1
• DOI: https://doi.org/10.1093/noajnl/vdab030
• Public URL: https://nottingham-repository.worktribe.com/output/5319365
• Publisher URL: https://academic.oup.com/noa/article/3/1/vdab030/6256722