A clinically compatible drug-screening platform based on organotypic cultures identifies vulnerabilities to prevent and treat brain metastasis.
drug-screen
metastasis
organotypic cultures
patient-derived
resistance
Journal
EMBO molecular medicine
ISSN: 1757-4684
Titre abrégé: EMBO Mol Med
Pays: England
ID NLM: 101487380
Informations de publication
Date de publication:
07 03 2022
07 03 2022
Historique:
revised:
22
12
2021
received:
14
05
2021
accepted:
07
01
2022
pubmed:
18
2
2022
medline:
15
3
2022
entrez:
17
2
2022
Statut:
ppublish
Résumé
We report a medium-throughput drug-screening platform (METPlatform) based on organotypic cultures that allows to evaluate inhibitors against metastases growing in situ. By applying this approach to the unmet clinical need of brain metastasis, we identified several vulnerabilities. Among them, a blood-brain barrier permeable HSP90 inhibitor showed high potency against mouse and human brain metastases at clinically relevant stages of the disease, including a novel model of local relapse after neurosurgery. Furthermore, in situ proteomic analysis applied to metastases treated with the chaperone inhibitor uncovered a novel molecular program in brain metastasis, which includes biomarkers of poor prognosis and actionable mechanisms of resistance. Our work validates METPlatform as a potent resource for metastasis research integrating drug-screening and unbiased omic approaches that is compatible with human samples. Thus, this clinically relevant strategy is aimed to personalize the management of metastatic disease in the brain and elsewhere.
Identifiants
pubmed: 35174975
doi: 10.15252/emmm.202114552
pmc: PMC8899920
doi:
Substances chimiques
Antineoplastic Agents
0
Banques de données
GEO
['GSE153173', 'GSE184869']
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
e14552Subventions
Organisme : NCI NIH HHS
ID : P30 CA015083
Pays : United States
Investigateurs
Adolfo de la Lama-Zaragoza
(A)
Lourdes Calero-Felix
(L)
Concepcion Fiaño-Valverde
(C)
Pedro David Delgado-López
(PD)
Antonio Montalvo-Afonso
(A)
Mar Pascual-Llorente
(M)
Ángela Díaz-Piqueras
(Á)
S H Nam-Cha
(SH)
Cristina Barrena López
(C)
Gerard Plans Ahicart
(G)
Elena Martínez-Saez
(E)
Santiago Ramón Y Cajal
(S)
Pilar Nicolás
(P)
Informations de copyright
© 2022 The Authors. Published under the terms of the CC BY 4.0 license.
Références
Am J Pathol. 2013 Jun;182(6):2368-79
pubmed: 23583652
Ann Oncol. 2021 Nov;32(11):1332-1347
pubmed: 34364998
Nat Med. 2015 Nov;21(11):1318-25
pubmed: 26479923
J Immunol. 2009 Oct 1;183(7):4385-94
pubmed: 19748980
Bioinformatics. 2015 Jan 15;31(2):166-9
pubmed: 25260700
Nat Rev Cancer. 2020 Jan;20(1):4-11
pubmed: 31780784
Nat Rev Cancer. 2005 Oct;5(10):761-72
pubmed: 16175177
Int J Clin Exp Pathol. 2019 Mar 01;12(3):978-986
pubmed: 31933908
Cancer Chemother Pharmacol. 1995;36(4):305-15
pubmed: 7628050
Lancet Oncol. 2013 Sep;14(10):e396-406
pubmed: 23993384
Anticancer Res. 2018 Mar;38(3):1551-1562
pubmed: 29491085
Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17456-61
pubmed: 21987811
Cancer Discov. 2015 Nov;5(11):1164-1177
pubmed: 26410082
Nat Rev Clin Oncol. 2020 May;17(5):279-299
pubmed: 32080373
Genome Biol. 2009;10(3):R25
pubmed: 19261174
Nat Rev Mol Cell Biol. 2017 Jun;18(6):345-360
pubmed: 28429788
Breast Cancer Res Treat. 2018 Apr;168(2):357-364
pubmed: 29198055
Int J Oncol. 2015 Jan;46(1):47-54
pubmed: 25351442
EMBO Mol Med. 2022 Mar 7;14(3):e14552
pubmed: 35174975
Cancer Res. 2020 Oct 15;80(20):4314-4323
pubmed: 32641416
Toxicol In Vitro. 2011 Apr;25(3):715-23
pubmed: 21184822
J Cell Mol Med. 2017 Aug;21(8):1532-1544
pubmed: 28211159
Nat Genet. 2018 Oct;50(10):1399-1411
pubmed: 30262818
N Engl J Med. 2000 Nov 9;343(19):1350-4
pubmed: 11070098
Genome Biol. 2014;15(12):550
pubmed: 25516281
Cancer Lett. 2012 May 28;318(2):180-8
pubmed: 22182451
Cancer Res. 2000 Nov 1;60(21):5954-8
pubmed: 11085511
N Engl J Med. 2005 Mar 10;352(10):997-1003
pubmed: 15758010
Cancer Res. 2007 Apr 1;67(7):2932-7
pubmed: 17409397
PLoS One. 2012;7(6):e39626
pubmed: 22737248
PLoS One. 2008 Mar 05;3(3):e0001722
pubmed: 18320023
Cancer Res. 2009 Sep 1;69(17):6995-7003
pubmed: 19690146
Neurosurgery. 2019 Mar 1;84(3):E152-E155
pubmed: 30629227
Nature. 2016 Jan 21;529(7586):351-7
pubmed: 26760213
Lancet Oncol. 2009 May;10(5):459-66
pubmed: 19269895
Bioinformatics. 2017 Jan 1;33(1):135-136
pubmed: 27605098
Cell Rep Med. 2020 Dec 22;1(9):100161
pubmed: 33377132
Trends Cancer. 2018 Mar;4(3):176-196
pubmed: 29506669
Ann N Y Acad Sci. 1997 Nov 3;834:600-8
pubmed: 9405871
J Natl Cancer Inst. 2018 Aug 1;110(8):914-917
pubmed: 29529211
Cancer Cell. 2020 Jan 13;37(1):85-103.e9
pubmed: 31935375
Lancet Oncol. 2013 Sep;14(10):e407-16
pubmed: 23993385
Lancet Oncol. 2018 Jan;19(1):e20-e32
pubmed: 29304358
Clin Cancer Res. 2016 Dec 15;22(24):6078-6087
pubmed: 27521448
Anticancer Res. 2016 May;36(5):2197-203
pubmed: 27127123
Bioinformatics. 2009 May 1;25(9):1105-11
pubmed: 19289445
Proc Natl Acad Sci U S A. 2005 Oct 25;102(43):15545-50
pubmed: 16199517
Nat Rev Cancer. 2017 Sep;17(9):528-542
pubmed: 28751651
Nat Rev Mol Cell Biol. 2014 Oct;15(10):647-64
pubmed: 25237826
Nat Commun. 2015 May 11;6:7007
pubmed: 25959678
Ann Oncol. 2008 Mar;19(3):590-4
pubmed: 18037622
Neuroscience. 2015 Oct 1;305:86-98
pubmed: 26254240
Glia. 2018 Nov;66(11):2438-2455
pubmed: 30357946
In Vitro Cell Dev Biol Anim. 2019 May;55(5):349-354
pubmed: 30989449
Nat Commun. 2020 Aug 4;11(1):3883
pubmed: 32753598
Clin Cancer Res. 2009 Jun 15;15(12):4046-57
pubmed: 19509149
Biochem Pharmacol. 2014 Feb 1;87(3):445-55
pubmed: 24291777
Neuro Oncol. 2021 Sep 1;23(9):1470-1480
pubmed: 33433612
Clin Cancer Res. 2014 May 1;20(9):2476-84
pubmed: 24634382
Lancet Oncol. 2015 Jun;16(6):e270-8
pubmed: 26065612
Pharmacol Res. 2021 Jan;163:105295
pubmed: 33176207
Nature. 2009 Jun 18;459(7249):1005-9
pubmed: 19421193
Nature. 2016 May 18;533(7604):493-498
pubmed: 27225120
Cell Death Dis. 2013 Oct 10;4:e838
pubmed: 24113172
Nat Rev Cancer. 2010 Aug;10(8):537-49
pubmed: 20651736
J Comp Neurol. 2001 Feb 5;430(2):250-63
pubmed: 11135260
Angiogenesis. 2020 Feb;23(1):3-8
pubmed: 31701335
Cold Spring Harb Perspect Med. 2017 Jul 5;7(7):
pubmed: 28213438
Oncotarget. 2016 Jan 19;7(3):2823-36
pubmed: 26673821
Cell. 2009 Jul 10;138(1):51-62
pubmed: 19576624
Nat Rev Cancer. 2014 Dec;14(12):801-14
pubmed: 25568920
Mol Cell. 2016 Nov 17;64(4):835-849
pubmed: 27818143
Bioinformatics. 2009 Aug 15;25(16):2078-9
pubmed: 19505943
J Natl Cancer Inst. 2019 Apr 1;111(4):388-398
pubmed: 29961873
Clin Cancer Res. 2000 Aug;6(8):3312-8
pubmed: 10955818
J Clin Oncol. 2010 Apr 10;28(11):1963-72
pubmed: 20231676
Curr Pharm Biotechnol. 2019;20(14):1163-1171
pubmed: 31433750
Elife. 2019 Mar 26;8:
pubmed: 30912515
EMBO Mol Med. 2019 Jul;11(7):e10292
pubmed: 31273934
Bioinformatics. 2012 Jun 15;28(12):i172-8
pubmed: 22689758
Neuro Oncol. 2016 Aug;18(8):1043-65
pubmed: 27382120
Nat Med. 2018 Jul;24(7):1024-1035
pubmed: 29892069
Int J Oncol. 2016 Apr;48(4):1710-20
pubmed: 26892093
Clin Cancer Res. 2012 Jan 1;18(1):64-76
pubmed: 22215907
Cell. 2014 Feb 27;156(5):1002-16
pubmed: 24581498
Nat Cell Biol. 2018 Aug;20(8):966-978
pubmed: 30038252
Nat Cell Biol. 2014 Sep;16(9):876-88
pubmed: 25086747
Cancer. 2020 Apr 1;126(7):1390-1406
pubmed: 31971613
N Engl J Med. 2005 Mar 10;352(10):987-96
pubmed: 15758009
Cell Rep. 2019 Nov 5;29(6):1645-1659.e9
pubmed: 31693902
Science. 2018 Feb 23;359(6378):920-926
pubmed: 29472484
Cell. 2019 Jan 10;176(1-2):43-55.e13
pubmed: 30528430