Mutant ACVR1 Arrests Glial Cell Differentiation to Drive Tumorigenesis in Pediatric Gliomas

Cancer Cell
Jerome FortinTak W Mak

Abstract

Diffuse intrinsic pontine gliomas (DIPGs) are aggressive pediatric brain tumors for which there is currently no effective treatment. Some of these tumors combine gain-of-function mutations in ACVR1, PIK3CA, and histone H3-encoding genes. The oncogenic mechanisms of action of ACVR1 mutations are currently unknown. Using mouse models, we demonstrate that Acvr1G328V arrests the differentiation of oligodendroglial lineage cells, and cooperates with Hist1h3bK27M and Pik3caH1047R to generate high-grade diffuse gliomas. Mechanistically, Acvr1G328V upregulates transcription factors which control differentiation and DIPG cell fitness. Furthermore, we characterize E6201 as a dual inhibitor of ACVR1 and MEK1/2, and demonstrate its efficacy toward tumor cells in vivo. Collectively, our results describe an oncogenic mechanism of action for ACVR1 mutations, and suggest therapeutic strategies for DIPGs.

References

Oct 10, 1998·Journal of Cellular Physiology·K TamakiP ten Dijke
Jul 3, 2002·Nature Reviews. Neuroscience·Nicolas BertrandFrançois Guillemot
Dec 2, 2004·Acta Crystallographica. Section D, Biological Crystallography·Paul Emsley, Kevin Cowtan
Dec 22, 2005·Acta Crystallographica. Section D, Biological Crystallography·Andrew G W Leslie
Mar 23, 2006·Acta Crystallographica. Section D, Biological Crystallography·Jay Painter, Ethan A Merritt
Apr 25, 2007·Nucleic Acids Research·Ian W DavisDavid C Richardson
Jan 4, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·John D CahoyBen A Barres
Jun 13, 2008·Nature Protocols·Thomas D Schmittgen, Kenneth J Livak
Aug 15, 2008·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Jason C DugasBen A Barres
Jan 24, 2009·Genesis : the Journal of Genetics and Development·Masakazu YamamotoDavid J Goldhamer
Aug 1, 2007·Journal of Applied Crystallography·Airlie J McCoyRandy J Read
Feb 4, 2010·Acta Crystallographica. Section D, Biological Crystallography·Paul D AdamsPeter H Zwart
Mar 4, 2011·Proceedings of the National Academy of Sciences of the United States of America·Michelle MonjePhilip A Beachy
Apr 5, 2011·Acta Crystallographica. Section D, Biological Crystallography·Martyn D WinnKeith S Wilson
Jan 31, 2012·Nature Genetics·Gang WuUNKNOWN St. Jude Children's Research Hospital–Washington University Pediatric Cancer Genome Project
Sep 15, 2012·The Journal of Biological Chemistry·Apirat ChaikuadAlex N Bullock
Oct 30, 2012·Bioinformatics·Alexander DobinThomas R Gingeras
Feb 6, 2013·Journal of Visualized Experiments : JoVE·Sebastian SchildgeChristian Schachtrup
Jun 7, 2013·The Journal of Neuroscience : the Official Journal of the Society for Neuroscience·Hiroko NakataniCarlos Parras
Jan 21, 2014·Nature Reviews. Cancer·Anna LasorellaAntonio Iavarone
Apr 4, 2014·Bioinformatics·Anthony M BolgerBjoern Usadel
Apr 8, 2014·Nature Genetics·Adam M FontebassoMark W Kieran
Apr 8, 2014·Nature Genetics·Kathryn R TaylorJacques Grill
Aug 20, 2014·Cancer Research·Kathryn R TaylorChris Jones
Sep 19, 2014·Nature Reviews. Cancer·Chris Jones, Suzanne J Baker
Dec 18, 2014·Genome Biology·Michael I LoveSimon Anders
May 6, 2015·Nature Medicine·Catherine S GrassoMichelle Monje
Sep 4, 2015·Science Translational Medicine·Sarah J HatsellAris N Economides
Dec 2, 2015·Proceedings of the National Academy of Sciences of the United States of America·Kyosuke HinoJunya Toguchida
Jan 7, 2016·Nature·Sang Bae LeeAnna Lasorella
Apr 7, 2016·Nature Communications·Hamid NikbakhtJavad Nazarian
May 18, 2016·Nature Communications·Robert A LindquistArturo Alvarez-Buylla

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Citations

Oct 3, 2020·International Journal of Molecular Sciences·Maya S Graham, Ingo K Mellinghoff
Jul 9, 2020·Human Molecular Genetics·Anders M LindrothMassimo Squatrito
Jan 7, 2021·Neuropathology : Official Journal of the Japanese Society of Neuropathology·Shinichiro MoriToru Iwaki
Jan 12, 2021·Chinese Neurosurgical Journal·Dilakshan SrikanthanJames T Rutka
Mar 7, 2021·Biomedicines·Francesc VenturaGonzalo Sanchez-Duffhues
Jun 4, 2021·Science Advances·Juan WangAmanda Saratsis
Jun 23, 2021·EBioMedicine·Gabrielle PriceConstantinos G Hadjipanayis
Aug 24, 2021·ACS Omega·Lisa Rooney, Chris Jones
Oct 8, 2021·Communications Biology·Josephine T DaubPatrick Kemmeren

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Datasets Mentioned

BETA
GSE142776

Methods Mentioned

BETA
flow cytometry
RNA-seq
immunoprecipitation
X-ray
xenograft
PCR
Tandem Repeat
antisense oligonucleotides
xenografts
transfection

Key Resources (RRID) Mentioned

CVCL_IT40
CVCL_VU70
CVCL_0063
CVCL_0188
IMSR_JAX
MGI

Software Mentioned

GraphPad Prism
RSEM
FastQC
MOSFLM
PHASER
SynergyFinder
Li
Phenix Refine
ImageJ
TLSMD

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