A distinct pattern of growth and RAC1 signaling in melanoma brain metastasis cells.
RAC1
brain
melanoma
metastasis
microenvironment
Journal
Neuro-oncology
ISSN: 1523-5866
Titre abrégé: Neuro Oncol
Pays: England
ID NLM: 100887420
Informations de publication
Date de publication:
06 04 2023
06 04 2023
Historique:
medline:
7
4
2023
pubmed:
3
9
2022
entrez:
2
9
2022
Statut:
ppublish
Résumé
Melanoma, the deadliest of skin cancers, has a high propensity to form brain metastases that are associated with a markedly worsened prognosis. In spite of recent therapeutic advances, melanoma brain lesions remain a clinical challenge, biomarkers predicting brain dissemination are not clear and differences with other metastatic sites are poorly understood. We examined a genetically diverse panel of human-derived melanoma brain metastasis (MBM) and extracranial cell lines using targeted sequencing, a Reverse Phase Protein Array, protein expression analyses, and functional studies in vitro and in vivo. Brain-specific genetic alterations were not detected; however, MBM cells in vitro displayed lower proliferation rates and MBM-specific protein expression patterns associated with proliferation, DNA damage, adhesion, and migration. MBM lines displayed higher levels of RAC1 expression, involving a distinct RAC1-PAK1-JNK1 signaling network. RAC1 knockdown or treatment with small molecule inhibitors contributed to a less aggressive MBM phenotype in vitro, while RAC1 knockdown in vivo led to reduced tumor volumes and delayed tumor appearance. Proliferation, adhesion, and migration were higher in MBM vs nonMBM lines in the presence of insulin or brain-derived factors and were affected by RAC1 levels. Our findings indicate that despite their genetic variability, MBM engage specific molecular processes such as RAC1 signaling to adapt to the brain microenvironment and this can be used for the molecular characterization and treatment of brain metastases.
Sections du résumé
BACKGROUND
Melanoma, the deadliest of skin cancers, has a high propensity to form brain metastases that are associated with a markedly worsened prognosis. In spite of recent therapeutic advances, melanoma brain lesions remain a clinical challenge, biomarkers predicting brain dissemination are not clear and differences with other metastatic sites are poorly understood.
METHODS
We examined a genetically diverse panel of human-derived melanoma brain metastasis (MBM) and extracranial cell lines using targeted sequencing, a Reverse Phase Protein Array, protein expression analyses, and functional studies in vitro and in vivo.
RESULTS
Brain-specific genetic alterations were not detected; however, MBM cells in vitro displayed lower proliferation rates and MBM-specific protein expression patterns associated with proliferation, DNA damage, adhesion, and migration. MBM lines displayed higher levels of RAC1 expression, involving a distinct RAC1-PAK1-JNK1 signaling network. RAC1 knockdown or treatment with small molecule inhibitors contributed to a less aggressive MBM phenotype in vitro, while RAC1 knockdown in vivo led to reduced tumor volumes and delayed tumor appearance. Proliferation, adhesion, and migration were higher in MBM vs nonMBM lines in the presence of insulin or brain-derived factors and were affected by RAC1 levels.
CONCLUSIONS
Our findings indicate that despite their genetic variability, MBM engage specific molecular processes such as RAC1 signaling to adapt to the brain microenvironment and this can be used for the molecular characterization and treatment of brain metastases.
Identifiants
pubmed: 36054930
pii: 6687782
doi: 10.1093/neuonc/noac212
pmc: PMC10076948
doi:
Substances chimiques
Biomarkers
0
RAC1 protein, human
0
rac1 GTP-Binding Protein
EC 3.6.5.2
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Research Support, N.I.H., Extramural
Langues
eng
Sous-ensembles de citation
IM
Pagination
674-686Subventions
Organisme : NCI NIH HHS
ID : P01 CA025874
Pays : United States
Organisme : NCI NIH HHS
ID : P30 CA010815
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA114046
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA221703
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA241490
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA047159
Pays : United States
Organisme : NCI NIH HHS
ID : R50 CA221675
Pays : United States
Informations de copyright
© The Author(s) 2022. Published by Oxford University Press on behalf of the Society for Neuro-Oncology.
Références
Cancer Res. 2020 Oct 15;80(20):4314-4323
pubmed: 32641416
Int J Cancer. 2012 Dec 1;131(11):2509-18
pubmed: 22447293
Neuro Oncol. 2021 Nov 2;23(11):1816-1817
pubmed: 34350960
Genes Dev. 2006 Aug 15;20(16):2149-82
pubmed: 16912270
Curr Diabetes Rev. 2013 Mar 1;9(2):102-16
pubmed: 23231032
Nat Cell Biol. 1999 Aug;1(4):242-8
pubmed: 10559923
Cell. 2012 Jul 20;150(2):251-63
pubmed: 22817889
Genes Dev. 2005 Jan 1;19(1):1-49
pubmed: 15630019
Clin Cancer Res. 2016 Dec 1;22(23):5818-5828
pubmed: 27307593
Clin Cancer Res. 2009 Dec 15;15(24):7538-7546
pubmed: 19996208
Nat Rev Cancer. 2020 Jan;20(1):4-11
pubmed: 31780784
Expert Opin Drug Saf. 2019 May;18(5):381-392
pubmed: 30977681
Nat Rev Dis Primers. 2019 Jan 17;5(1):5
pubmed: 30655533
Cancer Discov. 2019 Dec;9(12):1720-1735
pubmed: 31578185
Oncogene. 2014 Apr 3;33(14):1850-61
pubmed: 23624919
Front Cell Neurosci. 2014 Sep 25;8:307
pubmed: 25309333
Cell Death Dis. 2017 Mar 9;8(3):e2664
pubmed: 28277539
Proc Natl Acad Sci U S A. 2011 Oct 18;108(42):17456-61
pubmed: 21987811
Clin Cancer Res. 2014 Nov 1;20(21):5537-46
pubmed: 24803579
Cancer Res. 2014 Sep 1;74(17):4845-4852
pubmed: 25056119
Pigment Cell Melanoma Res. 2019 May;32(3):458-469
pubmed: 30712316
Mol Cell. 2011 Apr 8;42(1):50-61
pubmed: 21474067
J Signal Transduct. 2012;2012:365769
pubmed: 22175014
Neuro Oncol. 2022 Oct 3;24(10):1613-1646
pubmed: 35762249
Neurooncol Adv. 2021 Jan 06;3(1):vdaa177
pubmed: 33575655
Biochem Pharmacol. 2000 Oct 15;60(8):1015-21
pubmed: 11007936
Cell Rep. 2017 Nov 14;21(7):1953-1967
pubmed: 29141225
Biol Open. 2018 Jan 11;7(1):
pubmed: 29175861
Cell Rep. 2017 Nov 14;21(7):1936-1952
pubmed: 29141224
Cancer Res. 2002 Apr 1;62(7):2131-40
pubmed: 11929835
Cancer Discov. 2019 May;9(5):628-645
pubmed: 30787016
Cancers (Basel). 2021 Feb 10;13(4):
pubmed: 33578810
Nature. 2017 Oct 5;550(7674):133-136
pubmed: 28953887
J Neurosci. 2007 Aug 8;27(32):8604-15
pubmed: 17687038
Cancer Cell. 2017 Mar 13;31(3):326-341
pubmed: 28292436
Trends Cancer. 2020 Jun;6(6):478-488
pubmed: 32460002
Front Oncol. 2017 Sep 25;7:230
pubmed: 28993799
Cancer Res. 2006 Mar 15;66(6):3188-96
pubmed: 16540670
Acta Neuropathol. 2021 Feb;141(2):303-321
pubmed: 33394124
Melanoma Manag. 2020 Jun 08;7(2):MMT44
pubmed: 32821376
Cancer J. 2017 Jan/Feb;23(1):68-74
pubmed: 28114258
Mol Cancer Res. 2019 Sep;17(9):1787-1800
pubmed: 31138602
Int J Mol Sci. 2018 Nov 23;19(12):
pubmed: 30477115
Nat Commun. 2014 May 29;5:3887
pubmed: 24871328
JAMA Oncol. 2020 Dec 01;6(12):1957-1966
pubmed: 32970096
Exp Dermatol. 2022 Jan;31(1):31-42
pubmed: 33455008
Cell Syst. 2016 Jan 27;2(1):38-48
pubmed: 27136688
Br J Cancer. 2021 Jan;124(1):156-160
pubmed: 33024263
Proc Natl Acad Sci U S A. 2011 Nov 8;108(45):18289-94
pubmed: 22021442
Traffic. 2010 Jun;11(6):800-12
pubmed: 20230528