Post-translational Modifications of OLIG2 Regulate Glioma Invasion through the TGF-β Pathway

Singh, Shiv K.; Fiorelli, Roberto; Kupp, Robert; Rajan, Sindhu; Szeto, Emily; Cascio, Costanza Lo; Maire, Cécile L.; Sun, Yu; Alberta, John A.; Eschbacher, Jennifer; Ligon, Keith L.; Berens, Michael E.; Sanai, Nader; Mehta, Shwetal

doi:10.1016/j.celrep.2017.05.039

Cited by 4 publications

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“…Notably, we and others showed that a large population of OLIG2 + cells in human gliomas, particularly proneural GBMs, expresses the proliferative marker Ki67 and the stem-cell marker CD133, suggesting that proliferative OLIG2 + cells are tumor-propagating cells (Ligon et al, 2007;F. Lu et al, 2016;S. K. Singh et al, 2016).…”

Section: Oligodendrocyte Precursor Cellsmentioning

confidence: 73%

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Developmental origins and oncogenic pathways in malignant brain tumors

Qian

Zhou

2019

WIREs Developmental Biology

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Brain tumors such as adult glioblastomas and pediatric high-grade gliomas or medulloblastomas are among the leading causes of cancer-related deaths, exhibiting poor prognoses with little improvement in outcomes in the past several decades. These tumors are heterogeneous and can be initiated from various neural cell types, contributing to therapy resistance. How such heterogeneity arises is linked to the tumor cell of origin and their genetic alterations. Brain tumorigenesis and progression recapitulate key features associated with normal neurogenesis; however, the underlying mechanisms are quite dysregulated as tumor cells grow and divide in an uncontrolled manner. Recent comprehensive genomic, transcriptomic, and epigenomic studies at single-cell resolution have shed new light onto diverse tumor-driving events, cellular heterogeneity, and cells of origin in different brain tumors. Primary and secondary glioblastomas develop through different genetic alterations and pathways, such as EGFR amplification and IDH1/2 or TP53 mutation, respectively. Mutations such as histone H3K27M impacting epigenetic modifications define a distinct group of pediatric high-grade gliomas such as diffuse intrinsic pontine glioma. The identification of distinct genetic, epigenomic profiles and cellular heterogeneity has led to new classifications of adult and pediatric brain tumor subtypes, affording insights into molecular and lineage-specific vulnerabilities for treatment stratification. This review discusses our current understanding of tumor cells of origin, heterogeneity, recurring genetic and epigenetic alterations, oncogenic drivers and signaling pathways for adult glioblastomas, pediatric high-grade gliomas, and medulloblastomas, the genetically heterogeneous groups of malignant brain tumors.

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Section: Oligodendrocyte Precursor Cellsmentioning

confidence: 73%

“…Interestingly, OLIG2 appears to be ubiquitously expressed in human gliomas (Ligon et al, 2004; Q. R. Lu et al, 2001) and has a regulatory role in glioma initiation and tumor phenotype plasticity (Kupp et al, 2016;Ligon et al, 2007;F. Lu et al, 2016;S. K. Singh et al, 2016).…”

Section: Core Transcriptional Regulators Of Neurodevelopment and Tumorigenesis Crosstalkmentioning

confidence: 99%

Developmental origins and oncogenic pathways in malignant brain tumors

Qian

Zhou

2019

WIREs Developmental Biology

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“…Phosphorylation of this motif is developmentally regulated and it is the phosphorylated form of Olig2 that has gliomagenic and anti-p53 functions (Sun et al, 2011). A more recent study demonstrates that this phosphorylation also regulates the switch from the proliferation to invasion in glioma cells (Singh et al, 2016). In studies summarized here, we use mass spectrometry, genetics and test tube biochemistry with synthetic peptides to identify a set of three protein kinases that are collectively both necessary and sufficient to phosphorylate the triple serine motif.…”

Section: Introductionmentioning

confidence: 99%

Faculty Opinions recommendation of A sequentially priming phosphorylation cascade activates the gliomagenic transcription factor olig2.

Berry

2020

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature

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This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and review of the resulting proof before it is published in its final citable form. Please note that during the production process errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain. AUTHOR CONTRIBUTIONSJ.Z. identified the kinases involved in phosphorylating Olig2, A-C.T. tested Olig2 kinases in vivo in pediatric glioma model cells, J.A.A. did the in vitro kinase assays, S.B.F., J.D.C. and J.A.M. performed the mass spectrometry experiments, A.G. set up the mouse tumor system, J.S.D. provided technical assistance, M.M-S. and W.D.S. provided GSK3 knockout embryos, W.M. and P.S. provided the analog-specific kinase system and helpful discussions, K.L.L offered the human glioma cell lines, Y.S. and J.A.A. examined and analyzed the P-Olig2 levels in different p53 wild-type and p53 mutant glioma cell lines, R.H. and C.D.J. performed orthotopic survival study, and J.Z., D.H.R and C.D.S. designed the experiments and wrote the paper.

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Phenotype stability under dynamic brain-tumor environment stimuli maps glioblastoma progression in patients

2020

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Although tumor invasiveness is known to drive glioblastoma (GBM) recurrence, current approaches to treatment assume a fairly simple GBM phenotype transition map. We provide new analyses to estimate the likelihood of reaching or remaining in a phenotype under dynamic, physiologically likely perturbations of stimuli (“phenotype stability”). We show that higher stability values of the motile phenotype (Go) are associated with reduced patient survival. Moreover, induced motile states are capable of driving GBM recurrence. We found that the Dormancy and Go phenotypes are equally represented in advanced GBM samples, with natural transitioning between the two. Furthermore, Go and Grow phenotype transitions are mostly driven by tumor-brain stimuli. These are difficult to regulate directly, but could be modulated by reprogramming tumor-associated cell types. Our framework provides a foundation for designing targeted perturbations of the tumor-brain environment, by assessing their impact on GBM phenotypic plasticity, and is corroborated by analyses of patient data.

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Post-translational Modifications of OLIG2 Regulate Glioma Invasion through the TGF-β Pathway

Abstract: contributed RNA samples from pre-hypertrophic mouse models and assisted with computational analysis.

Cited by 4 publications

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Developmental origins and oncogenic pathways in malignant brain tumors

Developmental origins and oncogenic pathways in malignant brain tumors

Faculty Opinions recommendation of A sequentially priming phosphorylation cascade activates the gliomagenic transcription factor olig2.

Phenotype stability under dynamic brain-tumor environment stimuli maps glioblastoma progression in patients

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