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Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1–TGF-β–OTX2–SNAIL via PTEN inhibitio
Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy;European Sch Mol Med SEMM, Milan, Italy.
Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy;Hosp Sick Children, Arthur & Sonia Labatt Brain Tumour Res Ctr, Toronto, ON, Canada.
Univ Napoli Federico II, Dipartimento Med Mol & Biotecnol Med, Naples, Italy;CEINGE Biotecnol Avanzate, Naples, Italy.
CEINGE Biotecnol Avanzate, Naples, Italy.
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2018 (English)In: Brain, ISSN 0006-8950, E-ISSN 1460-2156, Vol. 141, no 5, p. 1300-1319Article in journal (Refereed) Published
Abstract [en]

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.

Place, publisher, year, edition, pages
2018. Vol. 141, no 5, p. 1300-1319
Keywords [en]
medulloblastoma, metastatic CNS tumour, molecular genetics, genetic network, oncology
National Category
Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-356501DOI: 10.1093/brain/awy039ISI: 000432177000017PubMedID: 29490009OAI: oai:DiVA.org:uu-356501DiVA, id: diva2:1236027
Funder
EU, FP7, Seventh Framework Programme, EU-FP7-TUMIC-HEALTH-F2-2008-2016662Available from: 2018-07-30 Created: 2018-07-30 Last updated: 2018-07-30Bibliographically approved

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