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

Veronica Ferrucci, Pasqualino De Antonellis, Francesco Paolo Pennino, Fatemeh Asadzadeh, Antonella Virgilio, Donatella Montanaro, Aldo Galeone, Iolanda Boffa, Ida Pisano, Iolanda Scognamiglio, Luigi Navas, Donatella DIana, Emilia Pedone, Sara Gargiulo, Matteo Gramanzini, Arturo Brunetti, Laura Danielson, Marianeve Carotenuto, Lucia Liguori, Antonio VerricoLucia Quaglietta, Maria Elena Errico, Valentina Del Monaco, Valeria D'Argenio, Felice Tirone, Angela Mastronuzzi, Vittoria Donofrio, Felice Giangaspero, Daniel Picard, Marc Remke, Livia Garzia, Craig Daniels, Olivier Delattre, Fredrik J. Swartling, William A. Weiss, Francesco Salvatore, Roberto Fattorusso, Louis Chesler, Michael D. Taylor, Giuseppe Cinalli, Massimo Zollo

Research output: Contribution to journalArticle

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. 10.1093/brain/awy039-video1 awy039media1 5742053534001

Original languageEnglish
Pages (from-to)1300-1319
Number of pages20
JournalBrain
Volume141
Issue number5
DOIs
Publication statusPublished - May 1 2018

Keywords

  • genetic network
  • medulloblastoma
  • metastatic CNS tumour
  • molecular genetics
  • oncology

ASJC Scopus subject areas

  • Clinical Neurology

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    Ferrucci, V., De Antonellis, P., Pennino, F. P., 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., ... Zollo, M. (2018). Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition. Brain, 141(5), 1300-1319. https://doi.org/10.1093/brain/awy039