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@ARTICLE{Nasir:168741,
      author       = {A. Nasir and A. Cardall and R. T. Othman and N. Nicolaou
                      and A. Lourdusamy and F. Linke and D. Onion and M. Ryzhova
                      and H. Cameron and C. Valente and A. Ritchie and A.
                      Korshunov$^*$ and S. M. Pfister$^*$ and A. M. Grabowska and
                      I. D. Kerr and B. Coyle},
      title        = {{ABCB}1 inhibition provides a novel therapeutic target to
                      block {TWIST}1-induced migration in medulloblastoma.},
      journal      = {Neuro-oncology advances},
      volume       = {3},
      number       = {1},
      issn         = {2632-2498},
      address      = {Oxford},
      publisher    = {Oxford University Press},
      reportid     = {DKFZ-2021-01035},
      pages        = {1-12},
      year         = {2021},
      note         = {3(1), 1–12, 2021},
      abstract     = {Therapeutic intervention in metastatic medulloblastoma is
                      dependent on elucidating the underlying metastatic
                      mechanism. We investigated whether an epithelial-mesenchymal
                      transition (EMT)-like pathway could drive medulloblastoma
                      metastasis.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 the morphology assessed by time-lapse imaging. Gene
                      expression was analyzed 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.Metastatic cells migrated to form large
                      metabolically active aggregates, whereas
                      non-tumorigenic/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 =
                      .041 and P = .04, respectively). High nuclear TWIST1
                      expression was observed in the invasive edge of the MED1
                      orthotopic model, and TWIST1 knockdown in cell lines was
                      associated with reduced cell migration (P < .05). TWIST1
                      bound to the ABCB1 promoter (P = .03) and induced cell
                      aggregation in metastatic and TWIST1-overexpressing,
                      non-metastatic (MED6-TWIST1) cells, which was significantly
                      attenuated by vardenafil (P < .05).In this study, we
                      identified a TWIST1-ABCB1 signaling axis during
                      medulloblastoma migration, which can be therapeutically
                      targeted with the clinically approved ABCB1 inhibitor,
                      vardenafil.},
      keywords     = {3D-BME model (Other) / ABCB1 (Other) / Harmine (Other) /
                      TWIST1 (Other) / epithelial–mesenchymal transition (Other)
                      / medulloblastoma (Other)},
      cin          = {B320 / B062},
      ddc          = {610},
      cid          = {I:(DE-He78)B320-20160331 / I:(DE-He78)B062-20160331},
      pnm          = {312 - Funktionelle und strukturelle Genomforschung
                      (POF4-312)},
      pid          = {G:(DE-HGF)POF4-312},
      typ          = {PUB:(DE-HGF)16},
      pubmed       = {pmid:33948561},
      pmc          = {pmc:PMC8080134},
      doi          = {10.1093/noajnl/vdab030},
      url          = {https://inrepo02.dkfz.de/record/168741},
}