TY - JOUR
T1 - Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition
AU - Ferrucci, Veronica
AU - de Antonellis, Pasqualino
AU - Pennino, Francesco Paolo
AU - Asadzadeh, Fatemeh
AU - Virgilio, Antonella
AU - Montanaro, Donatella
AU - Galeone, Aldo
AU - Boffa, Iolanda
AU - Pisano, Ida
AU - Scognamiglio, Iolanda
AU - Navas, Luigi
AU - Diana, Donatella
AU - Pedone, Emilia
AU - Gargiulo, Sara
AU - Gramanzini, Matteo
AU - Brunetti, Arturo
AU - Danielson, Laura
AU - Carotenuto, Marianeve
AU - Liguori, Lucia
AU - Verrico, Antonio
AU - Quaglietta, Lucia
AU - Errico, Maria Elena
AU - Del Monaco, Valentina
AU - D'Argenio, Valeria
AU - Tirone, Felice
AU - Mastronuzzi, Angela
AU - Donofrio, Vittoria
AU - Giangaspero, Felice
AU - Picard, Daniel
AU - Remke, Marc
AU - Garzia, Livia
AU - Daniels, Craig
AU - Delattre, Olivier
AU - Swartling, Fredrik J
AU - Weiss, William A
AU - Salvatore, Francesco
AU - Fattorusso, Roberto
AU - Chesler, Louis
AU - Taylor, Michael D
AU - Cinalli, Giuseppe
AU - Zollo, Massimo
PY - 2018/5/1
Y1 - 2018/5/1
N2 - 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.
AB - 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.
U2 - 10.1093/brain/awy039
DO - 10.1093/brain/awy039
M3 - Article
C2 - 29490009
VL - 141
SP - 1300
EP - 1319
JO - Brain
JF - Brain
SN - 0006-8950
IS - 5
ER -