Activation of mTORC1/mTORC2 signaling in pediatric low-grade glioma and pilocytic astrocytoma reveals mTOR as a therapeutic target

Hütt-Cabezas, Marianne; Karajannis, Matthias A.; Zagzag, David; Shah, Smit; Horkayne‐Szakaly, Iren; Rushing, Elisabeth J.; Cameron, J. Douglas; Jain, Deepali; Eberhart, Charles G.; Raabe, Eric H.; Rodríguez, Fausto J.

doi:10.1093/neuonc/not132

Cited by 67 publications

(77 citation statements)

References 34 publications

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“…In contrast, control astrocytes from a disease-free donor brain had a basal level of Rheb activation. Thus, we confirmed previous reports showing astrocytes derived from TSC cortical tubers are hyperactive for mTOR1/2 signalling (8).…”

Section: Resultssupporting

confidence: 92%

Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors

et al. 2016

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Inactivating mutations of the TSC1/TSC2 complex (TSC1/2) cause tuberous sclerosis (TSC), a hereditary syndrome with neurological symptoms and benign hamartoma tumours in the brain. Since TSC effectors are largely unknown in the human brain, TSC patient cortical tubers were used to uncover hyperphosphorylation unique to TSC primary astrocytes, the cell type affected in the brain. We found abnormal hyperphosphorylation of catenin delta-1 S268, which was reversible by mTOR- specific inhibitors. In contrast, in three metastatic astrocytoma cell lines, S268 was under phosphorylated, suggesting S268 phosphorylation controls metastasis. TSC astrocytes appeared epithelial (i.e. tightly adherent, less motile, and epithelial (E)-cadherin positive), whereas wild-type astrocytes were mesenchymal (i.e. E-cadherin negative and highly motile). Despite their epithelial phenotype, TSC astrocytes outgrew contact inhibition, and monolayers sporadically generated tuberous foci, a phenotype blocked by the mTOR inhibitor, Torin1. Also, mTOR-regulated phosphokinase C epsilon (PKCe) activity induced phosphorylation of catenin delta-1 S268, which in turn mediated cell-cell adhesion in astrocytes. The mTOR-dependent, epithelial phenotype of TSC astrocytes suggests TSC1/2 and mTOR tune the phosphorylation level of catenin delta-1 by controlling PKCe activity, thereby regulating the mesenchymal-epithelial-transition (MET). Thus, some forms of TSC could be treated with PKCe inhibitors, while metastasis of astrocytomas might be blocked by PKCe stimulators.

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Section: Resultssupporting

confidence: 92%

Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors

et al. 2016

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“…Studies reveal that the mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway is constitutively activated in the vast majority of PA. 12 The activation of mitogen-activated protein kinase/extracellular signal-regulated kinase signaling pathway may be associated with DNA alterations, such as NF1 deletion and mutation, v-raf murine sarcoma viral oncogene homolog B (KIAA1549/BRAF) fusion, SLIT-ROBO Rho GTPase activating protein 3 (SRGAP3/RAF1) fusion and BRAF V600E activating mutation. [6][7][8] In addition, mRNA expression aberrations have also been identified in the mammalian target of rapamycin, 13,14 phosphatidylinositol 3 kinase signaling pathway 15 or Matrilin 2 genes 10 in PA patients. Besides, DNA methylation is an epigenetic mechanism regulating gene expression.…”

Section: Introductionmentioning

confidence: 99%

Screening genes crucial for pediatric pilocytic astrocytoma using weighted gene coexpression network analysis combined with methylation data analysis

Zhao

Cai

et al. 2014

Cancer Gene Ther

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To identify novel genes associated with pediatric pilocytic astrocytoma (PA) for better understanding the molecular mechanism underlying the pediatric PA pathogenesis. Gene expression profile data of GSE50161 and GSE44971 and the methylation data of GSE44684 were downloaded from Gene Expression Omnibus. The differentially expressed genes (DEGs) between PA and normal control samples were screened using the limma package in R, and then used to construct weighted gene coexpression network (WGCN) using the WGCN analysis (WGCNA) package in R. Significant modules of DEGs were selected using the clustering analysis. Function enrichment analysis of the DEGs in significant modules were performed using the WGCNA package and clusterprofiler package in R. Correlation between methylation sites of DEGs and PA was analyzed using the CpGassoc package in R. Totally, 3479 DEGs were screened in PA samples. Thereinto, 3424 DEGs were used to construct the WGCN. Several significant modules of DEGs were selected based on the WGCN, in which the turquoise module was positively related to PA, whereas blue module was negatively related to PA. DEGs (for example, DOCK2 (dedicator of cytokinesis 2), DOCK8 and FCGR2A (Fc fragment of IgG, low affinity IIa)) in blue module were mainly involved in Fc gamma R-mediated phagocytosis pathway and natural killer cell-mediated cytotoxicity pathway. Methylations of 14 DEGs among the top 30 genes in blue module were related to PA. Our data suggest that DOCK2, DOCK8 and FCGR2A may represent potential therapeutic targets in PA that merits further investigation.

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“…Identifying other kinases that may also be actively involved in paediatric glioblastoma cell lines will also help to design appropriate combination strategies to enhance IGFR1 inhibitor treatment. Hütt-Cabezas has recently reviewed the topic in a paper titled 'Activation of mTORC1/mTORC2 signaling in pediatric low-grade glioma and pilocytic astrocytoma reveals mTOR as a therapeutic target', 32 and the importance of this pathway is also important in children with hematologic malignancies too. 33 Based on the pressing need to develop new inhibitors for mTOR, a number of researchers are currently identifying and developing novel small molecules against this, and related, targets.…”

Section: Igf1rmentioning

confidence: 99%

Approaches Toward Improving the Prognosis of Pediatric Patients With Glioma: Pursuing Mutant Drug Targets With Emerging Small Molecules

Snape

Warr

2015

Seminars in Pediatric Neurology

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Activation of mTORC1/mTORC2 signaling in pediatric low-grade glioma and pilocytic astrocytoma reveals mTOR as a therapeutic target

Cited by 67 publications

References 34 publications

Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors

Catenin delta-1 (CTNND1) phosphorylation controls the mesenchymal to epithelial transition in astrocytic tumors

Screening genes crucial for pediatric pilocytic astrocytoma using weighted gene coexpression network analysis combined with methylation data analysis

Approaches Toward Improving the Prognosis of Pediatric Patients With Glioma: Pursuing Mutant Drug Targets With Emerging Small Molecules

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