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

Veronica Ferrucci, Pasqualino de Antonellis, Francesco Paolo Pennino, Fatemeh Asadzadeh, Antonella Virgilio, Donatella Montanaro, Aldo Galeone, Iolanda Boffa, Ida Pisano, Iolanda Scognamiglio, Luigi Navas, Donatella Diana, Emilia Pedone, Sara Gargiulo, Matteo Gramanzini, Arturo Brunetti, Laura Danielson, Marianeve Carotenuto, Lucia Liguori, Antonio Verrico & 21 others Lucia Quaglietta, Maria Elena Errico, Valentina Del Monaco, Valeria D'Argenio, Felice Tirone, Angela Mastronuzzi, Vittoria Donofrio, Felice Giangaspero, Daniel Picard, Marc Remke, Livia Garzia, Craig Daniels, Olivier Delattre, Fredrik J Swartling, William A Weiss, Francesco Salvatore, Roberto Fattorusso, Louis Chesler, Michael D Taylor, Giuseppe Cinalli, Massimo Zollo

Research output: Contribution to journalArticle

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 languageEnglish
Pages (from-to)1300-1319
Number of pages20
JournalBrain : a journal of neurology
Volume141
Issue number5
DOIs
Publication statusPublished - May 1 2018

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Medulloblastoma
Up-Regulation
Exome
Heterografts
Neoplasms
Survival Rate
Pediatrics
Technology
Cell Line
Peptides
Mutation
Brain
Growth
Genes
Proteins

Cite this

Ferrucci, V., de Antonellis, P., Pennino, F. P., Asadzadeh, F., Virgilio, A., Montanaro, D., ... Zollo, M. (2018). Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition. Brain : a journal of neurology, 141(5), 1300-1319. https://doi.org/10.1093/brain/awy039

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 journalArticle

Ferrucci, V, de Antonellis, P, Pennino, FP, Asadzadeh, F, Virgilio, A, Montanaro, D, Galeone, A, Boffa, I, Pisano, I, Scognamiglio, I, Navas, L, Diana, D, Pedone, E, Gargiulo, S, Gramanzini, M, Brunetti, A, Danielson, L, Carotenuto, M, Liguori, L, Verrico, A, Quaglietta, L, Errico, ME, Del Monaco, V, D'Argenio, V, Tirone, F, Mastronuzzi, A, Donofrio, V, Giangaspero, F, Picard, D, Remke, M, Garzia, L, Daniels, C, Delattre, O, Swartling, FJ, Weiss, WA, Salvatore, F, Fattorusso, R, Chesler, L, Taylor, MD, Cinalli, G & Zollo, M 2018, 'Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition', Brain : a journal of neurology, vol. 141, no. 5, pp. 1300-1319. https://doi.org/10.1093/brain/awy039
Ferrucci V, de Antonellis P, Pennino FP, Asadzadeh F, Virgilio A, Montanaro D et al. Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition. Brain : a journal of neurology. 2018 May 1;141(5):1300-1319. https://doi.org/10.1093/brain/awy039
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. / Metastatic group 3 medulloblastoma is driven by PRUNE1 targeting NME1-TGF-β-OTX2-SNAIL via PTEN inhibition. In: Brain : a journal of neurology. 2018 ; Vol. 141, No. 5. pp. 1300-1319.
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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.",
author = "Veronica Ferrucci and {de Antonellis}, Pasqualino and Pennino, {Francesco Paolo} and Fatemeh Asadzadeh and Antonella Virgilio and Donatella Montanaro and Aldo Galeone and Iolanda Boffa and Ida Pisano and Iolanda Scognamiglio and Luigi Navas and Donatella Diana and Emilia Pedone and Sara Gargiulo and Matteo Gramanzini and Arturo Brunetti and Laura Danielson and Marianeve Carotenuto and Lucia Liguori and Antonio Verrico and Lucia Quaglietta and Errico, {Maria Elena} and {Del Monaco}, Valentina and Valeria D'Argenio and Felice Tirone and Angela Mastronuzzi and Vittoria Donofrio and Felice Giangaspero and Daniel Picard and Marc Remke and Livia Garzia and Craig Daniels and Olivier Delattre and Swartling, {Fredrik J} and Weiss, {William A} and Francesco Salvatore and Roberto Fattorusso and Louis Chesler and Taylor, {Michael D} and Giuseppe Cinalli and Massimo Zollo",
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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

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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

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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

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