An autocrine ActivinB mechanism drives TGFβ/Activin signaling in Group 3 medulloblastoma.
Animals
Antineoplastic Agents
/ pharmacology
Apoptosis
Autocrine Communication
Cell Line, Tumor
Cell Proliferation
Cerebellar Neoplasms
/ drug therapy
Female
Gene Expression Regulation, Neoplastic
Humans
Inhibin-beta Subunits
/ genetics
Medulloblastoma
/ drug therapy
Membrane Proteins
/ genetics
Mice, Nude
Phosphorylation
Pyrazoles
/ pharmacology
Quinolines
/ pharmacology
Signal Transduction
Smad2 Protein
/ metabolism
Smad3 Protein
/ metabolism
Transforming Growth Factor beta
/ genetics
Transforming Growth Factor beta1
/ genetics
Transforming Growth Factor beta3
/ genetics
Tumor Burden
Xenograft Model Antitumor Assays
Smad2
Smad3
TGFbeta
activin
medulloblastoma
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
08 2019
08 2019
Historique:
received:
19
09
2018
revised:
28
06
2019
accepted:
02
07
2019
pubmed:
23
7
2019
medline:
6
5
2020
entrez:
23
7
2019
Statut:
ppublish
Résumé
Medulloblastoma (MB) is a pediatric tumor of the cerebellum divided into four groups. Group 3 is of bad prognosis and remains poorly characterized. While the current treatment involving surgery, radiotherapy, and chemotherapy often fails, no alternative therapy is yet available. Few recurrent genomic alterations that can be therapeutically targeted have been identified. Amplifications of receptors of the TGFβ/Activin pathway occur at very low frequency in Group 3 MB. However, neither their functional relevance nor activation of the downstream signaling pathway has been studied. We showed that this pathway is activated in Group 3 MB with some samples showing a very strong activation. Beside genetic alterations, we demonstrated that an ActivinB autocrine stimulation is responsible for pathway activation in a subset of Group 3 MB characterized by high PMEPA1 levels. Importantly, Galunisertib, a kinase inhibitor of the cognate receptors currently tested in clinical trials for Glioblastoma patients, showed efficacy on orthotopically grafted MB-PDX. Our data demonstrate that the TGFβ/Activin pathway is active in a subset of Group 3 MB and can be therapeutically targeted.
Identifiants
pubmed: 31328883
doi: 10.15252/emmm.201809830
pmc: PMC6685082
doi:
Substances chimiques
Antineoplastic Agents
0
INHBB protein, human
0
Membrane Proteins
0
PMEPA1 protein, human
0
Pyrazoles
0
Quinolines
0
SMAD2 protein, human
0
SMAD3 protein, human
0
Smad2 Protein
0
Smad3 Protein
0
TGFB1 protein, human
0
TGFB3 protein, human
0
Transforming Growth Factor beta
0
Transforming Growth Factor beta1
0
Transforming Growth Factor beta3
0
LY-2157299
700874-72-2
Inhibin-beta Subunits
93443-12-0
Banques de données
GEO
['GSE85218']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e9830Subventions
Organisme : Ligue Contre le Cancer
ID : M18759
Pays : International
Organisme : Ligue Contre le Cancer
ID : M16649
Pays : International
Organisme : Ligue Contre le Cancer
ID : Leg Chovet
Pays : International
Organisme : Ministère Français de l'Enseignement Supérieur (MSRE)
Pays : International
Organisme : Fondation ARC pour la Recherche sur le Cancer (ARC)
Pays : International
Organisme : Institut National Du Cancer (INCa)
Pays : International
Informations de copyright
© 2019 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Cancer Cell. 2009 Apr 7;15(4):315-27
pubmed: 19345330
Mol Cell. 2010 Jan 15;37(1):123-34
pubmed: 20129061
Cytokine Growth Factor Rev. 2006 Feb-Apr;17(1-2):41-58
pubmed: 16310402
Mol Cell Biol. 2015 Dec 28;36(5):756-64
pubmed: 26711255
Cancer Sci. 2014 Mar;105(3):334-41
pubmed: 24438557
Nat Rev Neurol. 2012 May 08;8(6):340-51
pubmed: 22565209
Cancer Discov. 2014 Oct;4(10):1230-41
pubmed: 25084773
Brain. 2018 May 1;141(5):1300-1319
pubmed: 29490009
Dev Cell. 2009 Mar;16(3):329-43
pubmed: 19289080
Cancer Cell. 2015 Jun 8;27(6):809-21
pubmed: 25982816
Oncol Res. 1995;7(10-11):493-503
pubmed: 8866661
J Clin Oncol. 2011 Apr 10;29(11):1424-30
pubmed: 21098324
Elife. 2017 Feb 13;6:
pubmed: 28191871
Exp Biol Med (Maywood). 2002 Feb;227(2):75-87
pubmed: 11815670
Cancer Cell. 2017 Jun 12;31(6):737-754.e6
pubmed: 28609654
Stem Cells. 2011 Aug;29(8):1176-85
pubmed: 21630377
Cell Rep. 2018 Jun 26;23(13):3798-3812.e8
pubmed: 29949765
Cancer Cell. 2012 Feb 14;21(2):155-67
pubmed: 22340590
Genes Dev. 1994 Feb 15;8(4):414-27
pubmed: 8125256
Curr Treat Options Oncol. 2014 Dec;15(4):581-94
pubmed: 25194927
Cold Spring Harb Perspect Biol. 2017 Dec 1;9(12):
pubmed: 28246180
EMBO Mol Med. 2019 Aug;11(8):e9830
pubmed: 31328883
Lancet Oncol. 2017 Jul;18(7):958-971
pubmed: 28545823
Mol Cell. 2007 Nov 30;28(4):584-97
pubmed: 18042454
Proc Natl Acad Sci U S A. 1994 Sep 13;91(19):8817-21
pubmed: 8090730
Cancer Cell. 2018 Mar 12;33(3):435-449.e6
pubmed: 29533784
PLoS One. 2008 Aug 28;3(8):e3088
pubmed: 18769486
J Pathol. 2011 Apr;223(5):683-94
pubmed: 21341270
Nature. 2017 Jul 19;547(7663):311-317
pubmed: 28726821
Cancer Res. 2010 Aug 1;70(15):6377-83
pubmed: 20610632
Annu Rev Genomics Hum Genet. 2017 Aug 31;18:143-166
pubmed: 28475368
Mol Cell Biol. 1999 Sep;19(9):5913-22
pubmed: 10454538
Genes Dev. 2017 Sep 1;31(17):1738-1753
pubmed: 28971956
J Neurooncol. 2012 Dec;110(3):335-48
pubmed: 23054560
Acta Biochim Biophys Sin (Shanghai). 2016 Feb;48(2):194-201
pubmed: 26758191
Cancer Cell. 2007 Feb;11(2):147-60
pubmed: 17292826
Acta Neuropathol. 2012 Apr;123(4):465-72
pubmed: 22134537
Cell. 2008 Jul 25;134(2):215-30
pubmed: 18662538
Int J Biochem Cell Biol. 2008;40(3):383-408
pubmed: 18061509
Annu Rev Neurosci. 2018 Jul 8;41:207-232
pubmed: 29641939
Cancer Cell. 2010 Dec 14;18(6):655-68
pubmed: 21156287
Nature. 2016 Feb 4;530(7588):57-62
pubmed: 26814967
Dev Biol. 2009 Sep 15;333(2):273-84
pubmed: 19580801
Cancer Cell. 2018 Sep 10;34(3):396-410.e8
pubmed: 30205044
Cytokine Growth Factor Rev. 2013 Oct;24(5):477-84
pubmed: 23787160
Nature. 2014 Jul 24;511(7510):428-34
pubmed: 25043047
Nat Cell Biol. 2001 Apr;3(4):400-8
pubmed: 11283614
Neuropathol Appl Neurobiol. 2008 Jun;34(3):306-15
pubmed: 17995922
Cancer Cell. 2012 Feb 14;21(2):168-80
pubmed: 22340591
J Cell Sci. 2012 Sep 1;125(Pt 17):3929-37
pubmed: 22991378
Nat Rev Cancer. 2013 May;13(5):328-41
pubmed: 23612460
Lab Invest. 1991 Jun;64(6):833-43
pubmed: 1904513
Nature. 2012 Aug 2;488(7409):49-56
pubmed: 22832581
Cancer Cell. 2018 Sep 10;34(3):379-395.e7
pubmed: 30205043
Acta Biochim Biophys Sin (Shanghai). 2018 Jan 1;50(1):37-50
pubmed: 29228156
Cell Stem Cell. 2011 Nov 4;9(5):433-46
pubmed: 22056140