Evidence map›Paper›PMID 26826202›Full record

ArticleNeuro-oncology2016

Core pathway mutations induce de-differentiation of murine astrocytes into glioblastoma stem cells that are sensitive to radiation but resistant to temozolomide.

Ralf S Schmid, Jeremy M Simon, Mark Vitucci, Robert S McNeill, Ryan E Bash, Andrea M Werneke, Lauren Huey, Kristen K White, Matthew G Ewend, Jing Wu and 1 more

Open access · bronzeAbstract read
PubMed Full text at PMC Publisher
In one paragraph

Article in Neuro-oncology, 2016. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 32 papers.

0numbers the graph read from it
0cells of the map it votes in
32citing papers in PubMed
3.4field-weighted citation impact, top 8% of its field
1 · What the graph read from it

What it found

Each row is one number read from the abstract, on the scale the paper reported it, with its interval. Left of the dashed line favours the treatment, right favours the comparator. Under each row is the sentence it came from. New to these charts? A ten-minute tutorial.

The abstract states no effect estimate the extractor could read, or names no intervention and outcome on the map, so this paper lights no cell and moves no belief. It is still indexed, cited and linked below.

2 · The registry

The trial behind it

Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.

Neither the registry nor the abstract names a trial number. If this is a trial report, that itself is worth knowing.

3 · Its place in the literature

Who cites it

32 citing papers in PubMed, 34 citations in OpenAlex.

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  20. IncreasedGenes & development · 2018
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4 · The record

Corrections and comments

PubMed lists nothing against this paper. Absence here is not a guarantee, only a check that was made.

5 · Who and what money

Authors and funding

11 authors at 2 institutions in 1 country.

Ralf S SchmidLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
Jeremy M SimonLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
Mark VitucciLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
Robert S McNeillLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
Ryan E BashLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
Andrea M WernekeLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
Lauren HueyLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
Kristen K WhiteLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
Matthew G EwendLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
Jing WuLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
C Ryan MillerLineberger Comprehensive Cancer Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (R.S.S., L.H., M.G.E., J.W., C.R.M.); Division of Neuropathology, Department of Pathology & Laboratory Medicine, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.V., R.S.M., R.E.B., A.M.W., K.K.W., C.R.M.); Carolina Institute for Developmental Disabilities and Department of Genetics, University of North Carolina School of Medicine, Chapel Hill, North Carolina (J.M.S.); Department of Neurosurgery, University of North Carolina School of Medicine, Chapel Hill, North Carolina (M.G.E., J.W.); Department of Neurology and Neurosciences Center, University of North Carolina School of Medicine, Chapel Hill, North Carolina (C.R.M.).
UNC Lineberger Comprehensive Cancer CenterUniversity of North Carolina at Chapel Hill · US

Funding

Virology Research Program (Program 4)P30CA016086 · NCI · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Deborah F. Tate · 1985 to 2026
$201.5M
UNC-CH CENTER FOR ENVIRONMENTAL HEALTH &SUSCEPTIBILITYP30ES010126 · NIEHS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI Melissa A. Troester · 2001 to 2026
$36.3M
UNC Neuroscience Center Research Cores: MicroscopyP30NS045892 · NINDS · UNIV OF NORTH CAROLINA CHAPEL HILL · PI ZYLKA, MARK J. · 2003 to 2022
$11.5M
Howard Hughes Medical InstituteNCI NIH HHS P30 CA016086NIEHS NIH HHS P30 ES010126NINDS NIH HHS P30 NS045892
6 · The paper itself

Abstract

backgroundGlioma stem cells (GSCs) from human glioblastomas (GBMs) are resistant to radiation and chemotherapy and may drive recurrence. Treatment efficacy may depend on GSCs, expression of DNA repair enzymes such as methylguanine methyltransferase (MGMT), or transcriptome subtype.

methodsTo model genetic alterations in human GBM core signaling pathways, we induced Rb knockout, Kras activation, and Pten deletion mutations in cortical murine astrocytes. Neurosphere culture, differentiation, and orthotopic transplantation assays were used to assess whether these mutations induced de-differentiation into GSCs. Genome-wide chromatin landscape alterations and expression profiles were examined by formaldehyde-assisted isolation of regulatory elements (FAIRE) seq and RNA-seq. Radiation and temozolomide efficacy were examined in vitro and in an allograft model in vivo. Effects of radiation on transcriptome subtype were examined by microarray expression profiling.

resultsCultured triple mutant astrocytes gained unlimited self-renewal and multilineage differentiation capacity. These cells harbored significantly altered chromatin landscapes that were associated with downregulation of astrocyte- and upregulation of stem cell-associated genes, particularly the Hoxa locus of embryonic transcription factors. Triple-mutant astrocytes formed serially transplantable glioblastoma allografts that were sensitive to radiation but expressed MGMT and were resistant to temozolomide. Radiation induced a shift in transcriptome subtype of GBM allografts from proneural to mesenchymal.

conclusionA defined set of core signaling pathway mutations induces de-differentiation of cortical murine astrocytes into GSCs with altered chromatin landscapes and transcriptomes. This non-germline genetically engineered mouse model mimics human proneural GBM on histopathological, molecular, and treatment response levels. It may be useful for dissecting the mechanisms of treatment resistance and developing more effective therapies.

Indexed as

Drug Resistance, NeoplasmAnimalsAstrocytesBrain NeoplasmsCell DifferentiationCell Line, TumorDacarbazineGlioblastomaMice, TransgenicMutationNeoplastic Stem CellsSignal TransductionTemozolomideDacarbazineTemozolomideAstrocytesglioblastomaglioma stem cellsradiationtemozolomide

Identifiers

PMID26826202
PMCPMC4896545
OpenAlexW2258249884

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Registered trials

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Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.