Inhibition of microglial EZH2 leads to anti-tumoral effects in pediatric diffuse midline gliomas.
DIPG
EZH2
H3K27me3
anti-tumoral
microglia
Journal
Neuro-oncology advances
ISSN: 2632-2498
Titre abrégé: Neurooncol Adv
Pays: England
ID NLM: 101755003
Informations de publication
Date de publication:
Historique:
entrez:
6
9
2021
pubmed:
7
9
2021
medline:
7
9
2021
Statut:
epublish
Résumé
Diffuse intrinsic pontine gliomas (DIPG), within diffuse midline gliomas are aggressive pediatric brain tumors characterized by histone H3-K27M mutation. Small-molecule inhibitors for the EZH2-H3K27 histone methyltransferase have shown promise in preclinical animal models of DIPG, despite having little effect on DIPG cells Primary DIPG tissues, and cocultures between microglia and patient-derived DIPG or -pediatric high-grade glioma (pHGG) cell lines, were used to establish the H3-K27M status of each cell type. Antisense RNA strategies were used to target In primary DIPG tissues, microglia do not carry the H3-K27M mutation, otherwise characteristic of the cancer cells. Activation of a microglial tumor-supportive phenotype by pHGG, independently of their H3-K27M status, is associated with a transient H3K27me3 downregulation. Repression of EZH2 in DIPG cells has no impact on tumor cell survival or their ability to activate microglia. However, repression of EZH2 in microglia induces an anti-tumor phenotype resulting in decreased cancer cell invasion capability, increased microglial phagocytosis, and tumor-related cell death. These results indicate that microglia, beyond the tumor cells, contribute to the observed response of DIPG to EZH2 inhibition. Results highlight the potential importance of microglia as a new therapeutic avenue in DIPG.
Sections du résumé
BACKGROUND
BACKGROUND
Diffuse intrinsic pontine gliomas (DIPG), within diffuse midline gliomas are aggressive pediatric brain tumors characterized by histone H3-K27M mutation. Small-molecule inhibitors for the EZH2-H3K27 histone methyltransferase have shown promise in preclinical animal models of DIPG, despite having little effect on DIPG cells
METHODS
METHODS
Primary DIPG tissues, and cocultures between microglia and patient-derived DIPG or -pediatric high-grade glioma (pHGG) cell lines, were used to establish the H3-K27M status of each cell type. Antisense RNA strategies were used to target
RESULTS
RESULTS
In primary DIPG tissues, microglia do not carry the H3-K27M mutation, otherwise characteristic of the cancer cells. Activation of a microglial tumor-supportive phenotype by pHGG, independently of their H3-K27M status, is associated with a transient H3K27me3 downregulation. Repression of EZH2 in DIPG cells has no impact on tumor cell survival or their ability to activate microglia. However, repression of EZH2 in microglia induces an anti-tumor phenotype resulting in decreased cancer cell invasion capability, increased microglial phagocytosis, and tumor-related cell death.
CONCLUSIONS
CONCLUSIONS
These results indicate that microglia, beyond the tumor cells, contribute to the observed response of DIPG to EZH2 inhibition. Results highlight the potential importance of microglia as a new therapeutic avenue in DIPG.
Identifiants
pubmed: 34485907
doi: 10.1093/noajnl/vdab096
pii: vdab096
pmc: PMC8409254
doi:
Types de publication
Journal Article
Langues
eng
Pagination
vdab096Subventions
Organisme : Medical Research Council
ID : G0701018
Pays : United Kingdom
Organisme : Medical Research Council
ID : G1100578
Pays : United Kingdom
Organisme : Medical Research Council
ID : MR/N004272/1
Pays : United Kingdom
Informations de copyright
© The Author(s) 2021. Published by Oxford University Press, the Society for Neuro-Oncology and the European Association of Neuro-Oncology.
Références
Genes Dev. 2013 May 1;27(9):985-90
pubmed: 23603901
J Neurosurg Pediatr. 2018 Nov 30;23(3):308-316
pubmed: 30544362
Front Cell Neurosci. 2018 Aug 03;12:243
pubmed: 30123114
Acta Neuropathol. 2014;127(6):897-909
pubmed: 24777482
Nucleic Acids Res. 2010 Aug;38(15):4958-69
pubmed: 20385584
Nature. 2013 Oct 24;502(7472):462-71
pubmed: 24153299
Nat Commun. 2016 Apr 06;7:11185
pubmed: 27048880
Oncoimmunology. 2017 Oct 16;7(2):e1382790
pubmed: 29308302
Nat Genet. 2012 Jan 29;44(3):251-3
pubmed: 22286216
Nature. 2011 Apr 21;472(7343):319-24
pubmed: 21389984
J Clin Invest. 2021 Jan 4;131(1):
pubmed: 33108356
Mol Cancer Res. 2017 Sep;15(9):1243-1254
pubmed: 28522693
Cell Death Dis. 2019 Sep 11;10(9):671
pubmed: 31511494
Sci Transl Med. 2017 Mar 15;9(381):
pubmed: 28298418
Brain. 2017 Jun 1;140(6):1548-1560
pubmed: 28334886
Nat Med. 2017 Apr;23(4):493-500
pubmed: 28263307
Curr Neuropharmacol. 2017;15(1):88-97
pubmed: 27157264
Neuron. 2019 Nov 6;104(3):442-449
pubmed: 31697921
Elife. 2018 Jun 22;7:
pubmed: 29932419
Cancer Cell. 2017 Oct 9;32(4):520-537.e5
pubmed: 28966033
Front Cell Neurosci. 2018 Aug 03;12:235
pubmed: 30123112
Int J Mol Sci. 2020 Jan 13;21(2):
pubmed: 31940975
Front Pharmacol. 2019 Jun 05;10:506
pubmed: 31231208
Nat Rev Cancer. 2016 Dec;16(12):803-810
pubmed: 27658528
Neuro Oncol. 2017 Sep 1;19(9):1279-1280
pubmed: 28821206
Cell Rep. 2015 Mar 10;10(9):1626-1638
pubmed: 25753426
Int J Mol Sci. 2020 Nov 11;21(22):
pubmed: 33187183
Cancer Cell. 2013 Nov 11;24(5):660-72
pubmed: 24183680
Nat Med. 2017 Apr;23(4):483-492
pubmed: 28263309
Nature. 2017 Sep 28;549(7673):533-537
pubmed: 28959975
Klin Padiatr. 2016 Apr;228(3):113-7
pubmed: 27135271
Nat Neurosci. 2016 Jan;19(1):20-7
pubmed: 26713745
Nature. 2012 Jan 29;482(7384):226-31
pubmed: 22286061
Front Immunol. 2020 Sep 29;11:571951
pubmed: 33117364
Cell. 2015 May 7;161(4):803-16
pubmed: 25913192
Science. 2018 Apr 20;360(6386):331-335
pubmed: 29674595
Nat Med. 2016 Feb;22(2):128-34
pubmed: 26845405
Acta Neuropathol Commun. 2018 Jun 28;6(1):51
pubmed: 29954445
Acta Neuropathol. 2016 Jun;131(6):803-20
pubmed: 27157931
Expert Opin Ther Targets. 2020 Jul;24(7):605-614
pubmed: 32394767
Nat Immunol. 2016 Nov;17(11):1282-1290
pubmed: 27618552
Cell Biosci. 2017 Oct 30;7:56
pubmed: 29118968
Radiother Oncol. 2014 Apr;111(1):35-40
pubmed: 24560760
Neuro Oncol. 2019 Jan 1;21(1):83-94
pubmed: 30169876