Comparative single-cell RNA-sequencing profiling of BMP4-treated primary glioma cultures reveals therapeutic markers.
BMP
drug therapy
glioblastoma
single-cell RNA-sequencing
tumor heterogeneity
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
01 12 2022
01 12 2022
Historique:
pubmed:
1
6
2022
medline:
3
12
2022
entrez:
31
5
2022
Statut:
ppublish
Résumé
Glioblastoma (GBM) is the most aggressive primary brain tumor. Its cellular composition is very heterogeneous, with cells exhibiting stem-cell characteristics (GSCs) that co-determine therapy resistance and tumor recurrence. Bone Morphogenetic Protein (BMP)-4 promotes astroglial and suppresses oligodendrocyte differentiation in GSCs, processes associated with superior patient prognosis. We characterized variability in cell viability of patient-derived GBM cultures in response to BMP4 and, based on single-cell transcriptome profiling, propose predictive positive and early-response markers for sensitivity to BMP4. Cell viability was assessed in 17 BMP4-treated patient-derived GBM cultures. In two cultures, one highly-sensitive to BMP4 (high therapeutic efficacy) and one with low-sensitivity, response to treatment with BMP4 was characterized. We applied single-cell RNA-sequencing, analyzed the relative abundance of cell clusters, searched for and identified the aforementioned two marker types, and validated these results in all 17 cultures. High variation in cell viability was observed after treatment with BMP4. In three cultures with highest sensitivity for BMP4, a substantial new cell subpopulation formed. These cells displayed decreased cell proliferation and increased apoptosis. Neuronal differentiation was reduced most in cultures with little sensitivity for BMP4. OLIG1/2 levels were found predictive for high sensitivity to BMP4. Activation of ribosomal translation (RPL27A, RPS27) was up-regulated within one day in cultures that were very sensitive to BMP4. The changes in composition of patient-derived GBM cultures obtained after treatment with BMP4 correlate with treatment efficacy. OLIG1/2 expression can predict this efficacy, and upregulation of RPL27A and RPS27 are useful early-response markers.
Sections du résumé
BACKGROUND
Glioblastoma (GBM) is the most aggressive primary brain tumor. Its cellular composition is very heterogeneous, with cells exhibiting stem-cell characteristics (GSCs) that co-determine therapy resistance and tumor recurrence. Bone Morphogenetic Protein (BMP)-4 promotes astroglial and suppresses oligodendrocyte differentiation in GSCs, processes associated with superior patient prognosis. We characterized variability in cell viability of patient-derived GBM cultures in response to BMP4 and, based on single-cell transcriptome profiling, propose predictive positive and early-response markers for sensitivity to BMP4.
METHODS
Cell viability was assessed in 17 BMP4-treated patient-derived GBM cultures. In two cultures, one highly-sensitive to BMP4 (high therapeutic efficacy) and one with low-sensitivity, response to treatment with BMP4 was characterized. We applied single-cell RNA-sequencing, analyzed the relative abundance of cell clusters, searched for and identified the aforementioned two marker types, and validated these results in all 17 cultures.
RESULTS
High variation in cell viability was observed after treatment with BMP4. In three cultures with highest sensitivity for BMP4, a substantial new cell subpopulation formed. These cells displayed decreased cell proliferation and increased apoptosis. Neuronal differentiation was reduced most in cultures with little sensitivity for BMP4. OLIG1/2 levels were found predictive for high sensitivity to BMP4. Activation of ribosomal translation (RPL27A, RPS27) was up-regulated within one day in cultures that were very sensitive to BMP4.
CONCLUSION
The changes in composition of patient-derived GBM cultures obtained after treatment with BMP4 correlate with treatment efficacy. OLIG1/2 expression can predict this efficacy, and upregulation of RPL27A and RPS27 are useful early-response markers.
Identifiants
pubmed: 35639831
pii: 6593858
doi: 10.1093/neuonc/noac143
pmc: PMC9713526
doi:
Substances chimiques
Biomarkers
0
RNA
63231-63-0
BMP4 protein, human
0
Bone Morphogenetic Protein 4
0
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
2133-2145Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
Références
Cell Stem Cell. 2020 Jan 2;26(1):48-63.e6
pubmed: 31901251
J Mol Neurosci. 2016 Apr;58(4):497-506
pubmed: 26585989
Dev Biol. 2004 Dec 1;276(1):31-46
pubmed: 15531362
Cancer Discov. 2019 Dec;9(12):1708-1719
pubmed: 31554641
Neuro Oncol. 2020 Sep 29;22(9):1289-1301
pubmed: 32227096
Dev Biol. 2011 Feb 1;350(1):64-79
pubmed: 21094638
Nature. 2016 Nov 10;539(7628):309-313
pubmed: 27806376
Int J Cancer. 2020 Mar 1;146(5):1281-1292
pubmed: 31456217
Biochim Biophys Acta Mol Basis Dis. 2018 May;1864(5 Pt A):1850-1861
pubmed: 29486283
iScience. 2020 Mar 27;23(3):100882
pubmed: 32062421
Mol Cancer Res. 2020 Jul;18(7):981-991
pubmed: 32234828
Cell. 2019 Aug 8;178(4):835-849.e21
pubmed: 31327527
Stem Cells. 2009 Jan;27(1):7-17
pubmed: 18832593
Cell Rep. 2016 Jan 12;14(2):380-9
pubmed: 26748716
Neurosurg Rev. 2019 Jun;42(2):263-275
pubmed: 29138949
Sci Rep. 2019 Nov 22;9(1):17380
pubmed: 31758030
Nat Commun. 2019 Apr 16;10(1):1787
pubmed: 30992437
Mutat Res. 2010 Apr-Jun;704(1-3):12-20
pubmed: 20096807
Cell Death Dis. 2017 Oct 12;8(10):e3107
pubmed: 29022923
Neuro Oncol. 2016 Jul;18(7):928-38
pubmed: 26683138
Sci Rep. 2020 Feb 6;10(1):1970
pubmed: 32029822
Cell Stem Cell. 2017 Jan 5;20(1):120-134
pubmed: 28094016
Comput Biol Chem. 2020 Jun;86:107243
pubmed: 32172201
Methods Mol Biol. 2019;1869:79-84
pubmed: 30324515
Sci Rep. 2019 Oct 10;9(1):14569
pubmed: 31602000
Brain Pathol. 2016 Jan;26(1):43-61
pubmed: 25808628
Cancer Biother Radiopharm. 2011 Feb;26(1):77-83
pubmed: 21355779
Nat Cancer. 2021 Feb;2(2):141-156
pubmed: 33681822
Stem Cell Reports. 2015 Nov 10;5(5):829-842
pubmed: 26607953
Science. 2017 Mar 31;355(6332):
pubmed: 28360267
Nature. 2006 Dec 7;444(7120):761-5
pubmed: 17151667
Oncotarget. 2016 Apr 5;7(14):17920-31
pubmed: 26908439
Oncotarget. 2016 Jul 5;7(27):41959-41973
pubmed: 27259241
Front Cell Neurosci. 2013 Jun 04;7:87
pubmed: 23761735
Cancers (Basel). 2021 Apr 27;13(9):
pubmed: 33925547
BMC Neurosci. 2007 Jan 02;8:2
pubmed: 17199889
Amino Acids. 2006 Jun;30(4):445-51
pubmed: 16583319
Clin Cancer Res. 2010 May 15;16(10):2715-28
pubmed: 20442299
Cell. 2019 Jun 13;177(7):1888-1902.e21
pubmed: 31178118
J Clin Neurosci. 2018 Jan;47:28-42
pubmed: 29066236
Cancer Res. 2004 Oct 1;64(19):7011-21
pubmed: 15466194
Neuro Oncol. 2015 Oct;17 Suppl 4:iv1-iv62
pubmed: 26511214
Mol Cell Neurosci. 2000 Sep;16(3):185-96
pubmed: 10995546
Genes Dev. 2015 Jun 15;29(12):1203-17
pubmed: 26109046
Cancer Cell. 2010 Apr 13;17(4):362-75
pubmed: 20385361
Anal Biochem. 1987 Apr;162(1):156-9
pubmed: 2440339