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Rictor/mTORC2 signaling has opposing functions in adult glioma and childhood SHH medulloblastoma

ABSTRACT: Primary glioblastoma, representing over 90% of adult glioblastoma, develop rapidly without preexisting lower-grade glioma. We have generated a mouse model of primary glioblastoma driven by a single p53 mutation. These p53-mutant gliomas lose the syntenic region of human chromosome 10q, which is mapped to mouse chr19 and chr7. Loss of mouse chr19, containing Pten, activates PI3K/Akt signaling. Rictor/mTORC2 deletion inhibits Akt signaling, causing a significant delay in p53-mutant driven glioma formation. Unexpectedly, Rictor/mTORC2 loss promotes p53-mutant driven medulloblastomas with unique features of pediatric SHH medulloblastoma. Mechanistically, Rictor/mTORC2 loss inhibits the generation of glioma precursor cells from neural stem/progenitor cells in the adult brain, while causing a delay in differentiation of granule cell precursors in the developing brain, a cell-of-origin of SHH medulloblastoma.

ORGANISM(S): Mus musculus

PROVIDER: GSE78895 | GEO | 2018/06/01

REPOSITORIES: GEO

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Opposing tumor promoting and suppressive functions of Rictor/mTORC2 signaling in adult glioma and pediatric SHH medulloblastoma

Project description:Most human cancers arise from stem/progenitor cells by sequential accumulation of genetic/epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here we show that a single p53 mutation, despite causing no defect in mouse brain, promoted neural stem/progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas/glioblastomas with PI3K/Akt activation. Rictor/mTORC2 loss inhibited Akt signaling, greatly delaying and reducing glioma formation by suppressing glioma precursors within the subventricular zone stem-cell niche. Unexpectedly, Rictor/mTORC2 loss delayed timely differentiation of granule cell precursors (GCPs) during cerebellar development, promoting sustained GCP proliferation and medulloblastoma formation, which recapitulated critical features of TP53-mutant Sonic Hedgehog (SHH) medulloblastomas with GLI2 and/or N-MYC amplification. Our study demonstrates that Rictor/mTORC2 has opposing functions in neural stem cells and GCPs in the adult and developing brain, promoting malignant gliomas/glioblastoma and suppressing SHH-medulloblastoma formation, respectively.

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Murine models of IDH-wild-type glioblastoma exhibit spatial segregation of tumor initiation and manifestation during evolution

Project description:Primary glioblastoma, representing over 90% of adult glioblastoma, develop rapidly without preexisting lower-grade glioma. We have generated a mouse model of primary glioblastoma driven by a single p53 mutation. These p53-mutant gliomas lose the syntenic region of human chromosome 10q, which is mapped to mouse chr19 and chr7. Loss of mouse chr19, containing Pten, activates PI3K/Akt signaling. Using serial MRI/3D-reconstruction, whole-genome sequencing and spectral karyotyping-based single-cell phylogenetic tree building, we showed two distinct types of tumor evolution in p53-mutant driven mouse models. Malignant gliomas/GBMs grew as a single mass (Type 1) and multifocal masses (Type 2), respectively, despite both exhibiting loss of Pten/chromosome 19 (chr19) and PI3K/Akt activation with sub-tetraploid/4N genomes. Analysis of early biopsied and multi-segment tumor tissues revealed no evidence of less proliferative diploid/2N lesions in Type 1 tumors. Strikingly, CA-derived relatively quiescent tumor precursors with ancestral diploid/2N genomes and normal Pten/chr19 were observed in the subventricular zone (SVZ), but was distantly segregated from multi-focal Type 2 tumors. Importantly, PI3K/Akt inhibition by Rictor/mTORC2 deletion blocked distant dispersal, restricting glioma growth in the SVZ.

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Mus musculus

Project description:Rictor/mTORC2 signaling has opposing functions in adult glioma and childhood SHH medulloblastoma

| PRJNA314322 | ENA

Opposing tumor promoting and suppressive functions of Rictor/mTORC2 signaling in adult glioma and pediatric SHH medulloblastoma

Project description:Opposing tumor promoting and suppressive functions of Rictor/mTORC2 signaling in adult glioma and pediatric SHH medulloblastoma

| PRJNA476243 | ENA

Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure

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Deletion of Rictor in brain and fat alters peripheral clock gene expression and increases blood pressure

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