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.
| Original language | English |
|---|---|
| Pages (from-to) | 1300-1319 |
| Number of pages | 20 |
| Journal | Brain : a journal of neurology |
| Volume | 141 |
| Issue number | 5 |
| DOIs | |
| Publication status | Published - May 1 2018 |
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Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition. / Ferrucci, Veronica; de Antonellis, Pasqualino; Pennino, Francesco Paolo; Asadzadeh, Fatemeh; Virgilio, Antonella; Montanaro, Donatella; Galeone, Aldo; Boffa, Iolanda; Pisano, Ida; Scognamiglio, Iolanda; Navas, Luigi; Diana, Donatella; Pedone, Emilia; Gargiulo, Sara; Gramanzini, Matteo; Brunetti, Arturo; Danielson, Laura; Carotenuto, Marianeve; Liguori, Lucia; Verrico, Antonio; Quaglietta, Lucia; Errico, Maria Elena; Del Monaco, Valentina; D'Argenio, Valeria; Tirone, Felice; Mastronuzzi, Angela; Donofrio, Vittoria; Giangaspero, Felice; Picard, Daniel; Remke, Marc; Garzia, Livia; Daniels, Craig; Delattre, Olivier; Swartling, Fredrik J; Weiss, William A; Salvatore, Francesco; Fattorusso, Roberto; Chesler, Louis; Taylor, Michael D; Cinalli, Giuseppe; Zollo, Massimo.
In: Brain : a journal of neurology, Vol. 141, No. 5, 01.05.2018, p. 1300-1319.Research output: Contribution to journal › Article
}
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
VL - 141
SP - 1300
EP - 1319
JO - Brain
JF - Brain
SN - 0006-8950
IS - 5
ER -