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

Abstract Ämnesord

Stäng

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.

Av författaren/redakt...: Ferrucci, Veroni ...; de Antonellis, P ...; Pennino, Frances ...; Asadzadeh, Fatem ...; Virgilio, Antone ...; Montanaro, Donat ...; visa fler...; Galeone, Aldo; Boffa, Iolanda; Pisano, Ida; Scognamiglio, Io ...; Navas, Luigi; Diana, Donatella; Pedone, Emilia; Gargiulo, Sara; Gramanzini, Matt ...; Brunetti, Arturo; Danielson, Laura; Carotenuto, Mari ...; Liguori, Lucia; Verrico, Antonio; Quaglietta, Luci ...; Errico, Maria El ...; Del Monaco, Vale ...; D'Argenio, Valer ...; Tirone, Felice; Mastronuzzi, Ang ...; Donofrio, Vittor ...; Giangaspero, Fel ...; Picard, Daniel; Remke, Marc; Garzia, Livia; Daniels, Craig; Delattre, Olivie ...; Johansson, Fredr ...; Weiss, William A ...; Salvatore, Franc ...; Fattorusso, Robe ...; Chesler, Louis; Taylor, Michael ...; Cinalli, Giusepp ...; Zollo, Massimo; visa färre...

Om ämnet

MEDICIN OCH HÄLSOVETENSKAP: MEDICIN OCH HÄLS ...; och Klinisk medicin; och Cancer och onkol ...

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