Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition.

Brain. 2018 Feb 27;:

Authors: Ferrucci V, de Antonellis P, Pennino FP, Asadzadeh F, Virgilio A, Montanaro D, Galeone A, Boffa I, Pisano I, Scognamiglio I, Navas L, Diana D, Pedone E, Gargiulo S, Gramanzini M, Brunetti A, Danielson L, Carotenuto M, Liguori L, Verrico A, Quaglietta L, Errico ME, Del Monaco V, D'Argenio V, Tirone F, Mastronuzzi A, Donofrio V, Giangaspero F, Picard D, Remke M, Garzia L, Daniels C, Delattre O, Swartling FJ, Weiss WA, Salvatore F, Fattorusso R, Chesler L, Taylor MD, Cinalli G, Zollo M

Abstract
Genetic modifications during development of paediatric groups 3 and 4 medulloblastoma are responsible for their highly metastatic properties and poor patient survival rates. PRUNE1 is highly expressed in metastatic medulloblastoma group 3, which is characterized by TGF-β signalling activation, c-MYC amplification, and OTX2 expression. We describe the process of activation of the PRUNE1 signalling pathway that includes its binding to NME1, TGF-β activation, OTX2 upregulation, SNAIL (SNAI1) upregulation, and PTEN inhibition. The newly identified small molecule pyrimido-pyrimidine derivative AA7.1 enhances PRUNE1 degradation, inhibits this activation network, and augments PTEN expression. Both AA7.1 and a competitive permeable peptide that impairs PRUNE1/NME1 complex formation, impair tumour growth and metastatic dissemination in orthotopic xenograft models with a metastatic medulloblastoma group 3 cell line (D425-Med cells). Using whole exome sequencing technology in metastatic medulloblastoma primary tumour cells, we also define 23 common 'non-synonymous homozygous' deleterious gene variants as part of the protein molecular network of relevance for metastatic processes. This PRUNE1/TGF-β/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.

PMID: 29490009 [PubMed - as supplied by publisher]

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