PXD020242

PXD020242 is an original dataset announced via ProteomeXchange.

Title	Non-canonical EphA2 signaling is a driver of tumor-endothelial cell interactions and metastatic dissemination in BRAF inhibitor resistant melanoma: Expression Proteomics
Description	Acquired BRAF/MEK inhibitor resistance in melanoma results in a new transcriptional state associated with increased risk of metastasis. Here, we identified non-canonical EphA2 signaling as a driver of the resistance-associated metastatic state. We used mass spectrometry-based proteomic and phenotypic assays to demonstrate that the expression of active non-canonical EphA2-S897E in melanoma cells led to a mesenchymal-to-amoeboid transition (MAT) driven by Cdc42 activation. The induction of MAT promoted melanoma cell invasion, survival under shear stress, adhesion to endothelial cells under continuous flow conditions, increased permeability of endothelial cell monolayers and stimulated melanoma transendothelial cell migration. In vivo, melanoma cells expressing EphA2-S897E or active Cdc42 showed superior lung retention following tail-vain injection. Analysis of BRAF inhibitor-sensitive and -resistant melanoma cells demonstrated resistance to be associated with an MAT switch, upregulation of Cdc42 activity, increased invasion, and transendothelial migration. The drug resistant metastatic state was dependent upon histone deacetylase 8 (HDAC8) activity. Silencing of HDAC8 lead to inhibition of EphA2 and AKT phosphorylation, reduced invasion and impaired melanoma cell-endothelial cell interactions. In summary, we have demonstrated that the metastatic state associated with acquired BRAF inhibitor resistance is dependent on non-canonical EphA2 signaling, leading to increased melanoma-endothelial cell interactions and enhanced tumor dissemination.
HostingRepository	PRIDE
AnnounceDate	2020-11-18
AnnouncementXML	Submission_2020-11-18_03:46:25.xml
DigitalObjectIdentifier	https://dx.doi.org/10.6019/PXD020242
ReviewLevel	Peer-reviewed dataset
DatasetOrigin	Original dataset
RepositorySupport	Supported dataset by repository
PrimarySubmitter	John Koomen
SpeciesList	scientific name: Homo sapiens (Human); NCBI TaxID: 9606;
ModificationList	TMT6plex-126 reporter+balance reagent acylated residue; monohydroxylated residue; iodoacetamide derivatized residue
Instrument	Q Exactive

Revision	Datetime	Status	ChangeLog Entry
0	2020-07-07 16:20:24	ID requested
⏵ 1	2020-11-18 03:46:27	announced

Zhang C, Smalley I, Emmons MF, Sharma R, Izumi V, Messina J, Koomen JM, Pasquale EB, Forsyth PA, Smalley KSM, Resistant Melanoma. J Invest Dermatol, 141(4):840-851.e4(2021) [pubmed]

submitter keyword: Melanoma, Expression Proteomics. Ephrin A2, BRAF Inhibitor, Drug Resistance

Keiran Smalley, PhD
contact affiliation	Moffitt Cancer Center Tampa, FL, USA
contact email	keiran.smalley@moffitt.org
lab head
John Koomen
contact affiliation	Moffitt Cancer Center
contact email	john.koomen@moffitt.org
dataset submitter

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PRIDE project URI

• PRIDE
  1. PXD020242
     1. Label: PRIDE project
     2. Name: Non-canonical EphA2 signaling is a driver of tumor-endothelial cell interactions and metastatic dissemination in BRAF inhibitor resistant melanoma: Expression Proteomics