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

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.

A Signaling Network based Computational Model to Uncover Loop as the Novel Molecular Mechanisms for Medulloblastoma

“…after reducing OTX2 level [22]. In the same work, it is also reported that OTX2 level is positively correlated with TGF-signaling activity.…”

“…Even though the behaviors of subroutines that could activate MYC are not mentioned [22], we still investigate the simulated behaviors of those subroutines after OTX2 silencing in our study.…”

An autocrine ActivinB mechanism drives TGF β/Activin signaling in Group 3 medulloblastoma

“…While activation of the TGFβ/Activin pathway has been described in SHH group, no data are currently available regarding its activation in Group 3. A recent report showed that Prune‐1 may activate the TGFβ pathway in Group 3 MB but the level of pathway activation in Group 3 was not investigated nor its functional relevance (Ferrucci et al , ). It has also been suggested that TGFβ ligands determine the promigratory potential of bFGF signaling in MB but this study was performed in non‐Group 3 cell lines and in atypical MB‐PDX (Santhana Kumar et al , ).…”

“…In general, this signaling pathway reduces MYC expression (Warner et al , ; Seoane et al , ), although it can be induced in human embryonic stem cells (Brown et al , ). Since OTX2 has been demonstrated to be a major Smad2/3 target gene in the nervous system (Jia et al , ), it has been proposed to be a Smad2/3 inducible gene in Group 3 MB (Ferrucci et al , ) and considered as part of this signaling pathway in MB (Northcott et al , ). We did not detect any consistent changes in MYC and OTX2 expression upon modulation of the Activin pathway, suggesting that this signaling pathway does not regulate these two genes in Group 3 tumors and promotes tumor growth through other mechanisms.…”

Evaluation of the expression and distribution of Prune‐1 in the skin of healthy dogs

“…Dear Editors, Prune-1 is a member of the DHH (Asp-His-His) phosphoesterase protein superfamily involved in the regulation of cell proliferation and migration. [1][2][3] In humans, the gene Prune-1 is located in the 1q21.3 chromosomal region (epidermal differentiation complex) making it a good candidate for skin proliferation/differentiation and regulation. In a transgenic mouse model characterized by cutaneous hyper-proliferation, H-prune-1 has been associated with epidermal proliferation and keratinocyte differentiation, increased expression of pro-inflammatory cytokines and alteration of the skin barrier.…”