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Brain. 2018 May 1;141(5):1300-1319. doi: 10.1093/brain/awy039.

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

Author information

1
Dipartimento di Medicina Molecolare e Biotecnologie Mediche, Università degli Studi di Napoli Federico II, Naples, Italy.
2
CEINGE Biotecnologie Avanzate, Naples, Italy.
3
European School of Molecular Medicine (SEMM), Milan, Italy.
4
Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Ontario, Canada.
5
Dipartimento di Farmacia, Università degli Studi di Napoli Federico II, Naples, Italy.
6
Department of Veterinary Medicine and Animal Productions, Università degli Studi di Napoli Federico II, Naples, Italy.
7
Istituto di Biostrutture e Bioimmagini, Consiglio Nazionale della Ricerca, Naples, Italy.
8
Dipartimento di Scienze Biomediche Avanzate, Università degli Studi di Napoli Federico II, Naples, Italy.
9
Division of Clinical Studies, The Institute of Cancer Research, London SM2 5NG, UK.
10
Paediatric Neurosurgery, Ospedale Santobono-Pausilipon, Naples, Italy.
11
Pathology Unit, Ospedale Santobono-Pausilipon, Naples, Italy.
12
Genetic Control of Development-URT, Institute of Cell Biology and Neurobiology, National Research Council, Fondazione Santa Lucia, Rome, Italy.
13
Dipartimento di Onco-Ematologia, IRCCS Ospedale Pediatrico Bambino Gesù, Rome, Italy.
14
Dipartimento di Scienze Radiologiche, Oncologiche e Anatomo Patologiche, Università La Sapienza, Rome, Italy.
15
IRCCS Neuromed, Pozzilli, Italy.
16
German Cancer Consortium (DKTK), Department of Paediatric Oncology, Haematology, and Clinical Immunology, University Hospital Düsseldorf, Düsseldorf, Germany.
17
Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto ON, Canada.
18
PSL Research University, Inserm U830, Equipe Labellisée Ligue contre le Cancer, Institut Curie, Paris, France.
19
Department of Immunology, Genetics and Pathology, Uppsala University, Uppsala, Sweden.
20
Department of Neurology, University of California, San Francisco, San Francisco, CA, USA.
21
Dipartimento di Scienze e Tecnologie Ambientali, Biologiche e Farmaceutiche, Caserta, Italy.
22
DAI-Medicina Trasfusionale-Azienda Ospedaliera Universitaria Federico II, Naples, Italy.

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_video1awy039media15742053534001.

PMID:
29490009
DOI:
10.1093/brain/awy039
[Indexed for MEDLINE]

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