Journal
BRAIN
Volume 141, Issue -, Pages 1300-1319Publisher
OXFORD UNIV PRESS
DOI: 10.1093/brain/awy039
Keywords
medulloblastoma; metastatic CNS tumour; molecular genetics; genetic network; oncology
Categories
Funding
- Fondazione Adolfo Volpe e Associazione Pediatri di Famiglia [EU-FP7-TUMIC-HEALTH-F2-2008-2016662]
- Italian Association for Cancer research (AIRC) [11963]
- Regione Campania [5]
- European National Funds [PON01-02388/1 2007-2013]
- POR Rete delle Biotecnologie in Campania Movie
- European School of Molecular Medicine (SEMM)
- iCARE International AIRC felllowship
- DMMBM Federico II fellowship
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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-beta 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-beta 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-beta/OTX2/PTEN axis, together with the medulloblastoma-driver mutations, is of relevance for future rational and targeted therapies for metastatic medulloblastoma group 3.
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