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Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas 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. 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 the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively.

Glioblastoma (GBM) harbors subpopulations of therapy-resistant tumor-initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397 kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes in vitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we found that ZFHX4 significantly affects CHD4-mediated gene expression perturbations, which defines ZFHX4 as a master regulator of CHD4. These observations define ZFHX4 as a regulatory factor that links the chromatin-remodeling NuRD complex and the GBM TIC state.

Summary: Most human cancers arise from stem and progenitor cells by the sequential accumulation of genetic and epigenetic alterations, while cancer modeling typically requires simultaneous multiple oncogenic events. Here, we show that a single p53 mutation, despite causing no defect in the mouse brain, promoted neural stem and progenitor cells to spontaneously accumulate oncogenic alterations, including loss of multiple chromosomal (chr) regions syntenic to human chr10 containing Pten, forming malignant gliomas 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. 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 the developing brain, promoting malignant gliomas and suppressing SHH-medulloblastoma formation, respectively. : Hyperactivation of PI3K/AKT signaling is frequently observed in adult glioblastomas (GBMs), whereas sonic hedgehog-subgroup medulloblastomas (SHH-MBs) in children rarely exhibit AKT activation. Using a genetically engineered mouse model of malignant brain tumor, Akgül et al. show that Rictor/mTORC2 loss inhibits Akt signaling, which delays p53-mutant-driven malignant gliomas, while promoting SHH-MBs. Keywords: glioblastoma, medulloblastoma, Rictor, mammalian target of rapamycin complex 2, mTORC2, Pten, p53, phosphatidylinositol 3-kinase pathway, PI3K, Akt

As the list of putative driver mutations in glioma grows, we are just beginning to elucidate the effects of dysregulated developmental signaling pathways on the transformation of neural cells. We have employed a postnatal, mosaic, autochthonous glioma model that captures the first hours and days of gliomagenesis in more resolution than conventional genetically engineered mouse models of cancer. We provide evidence that disruption of the Nf1-Ras pathway in the ventricular zone at multiple signaling nodes uniformly results in rapid neural stem cell depletion, progenitor hyperproliferation, and gliogenic lineage restriction. Abolishing Ets subfamily activity, which is upregulated downstream of Ras, rescues these phenotypes and blocks glioma initiation. Thus, the Nf1-Ras-Ets axis might be one of the select molecular pathways that are perturbed for initiation and maintenance in glioma.

Glioblastoma (GBM) harbors subpopulations of therapy-resistant tumor-initiating cells (TICs) that are self-renewing and multipotent. To understand the regulation of the TIC state, we performed an image-based screen for genes regulating GBM TIC maintenance and identified ZFHX4, a 397 kDa transcription factor. ZFHX4 is required to maintain TIC-associated and normal human neural precursor cell phenotypes in vitro, suggesting that ZFHX4 regulates differentiation, and its suppression increases glioma-free survival in intracranial xenografts. ZFHX4 interacts with CHD4, a core member of the nucleosome remodeling and deacetylase (NuRD) complex. ZFHX4 and CHD4 bind to overlapping sets of genomic loci and control similar gene expression programs. Using expression data derived from GBM patients, we found that ZFHX4 significantly affects CHD4-mediated gene expression perturbations, which defines ZFHX4 as a master regulator of CHD4. These observations define ZFHX4 as a regulatory factor that links the chromatin-remodeling NuRD complex and the GBM TIC state.