ArticleThe Journal of investigative dermatology2021
Noncanonical EphA2 Signaling Is a Driver of Tumor-Endothelial Cell Interactions and Metastatic Dissemination in BRAF Inhibitor‒Resistant Melanoma.
Article in The Journal of investigative dermatology, 2021. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 21 papers.
What it found
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The trial behind it
Trials whose registry record cites this paper, or whose number appears in the abstract. A trial that started after this paper was published is citing it as background, not reporting it.
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Who cites it
21 citing papers in PubMed, 28 citations in OpenAlex.
- ANXA1-Derived Peptide Increases Melanoma Cell Sensitivity to Vemurafenib by Downregulating EphA2.Journal of cellular and molecular medicine · 2026Article
- Single-cell transcriptomics profiling elucidates RBP-driven metastatic signaling pathways in ERiScience · 2026Article
- The immune landscape of melanoma microenvironmental crosstalk.Frontiers in immunology · 2026Review
- EphA2 regulates vascular permeability and prostate cancer metastasis via modulation of cell junction protein phosphorylation.Oncogene · 2025Article
- Eph-ephrin signaling affects lens growth and shape, nucleus size, and gradient refractive index in adult mice.Frontiers in ophthalmology · 2025Article
- Eph/ephrin-mediated immune modulation: a potential therapeutic target.Frontiers in immunology · 2025Review
- Article
- Targeting EphA2: a promising strategy to overcome chemoresistance and drug resistance in cancer.Journal of molecular medicine (Berlin, Germany) · 2024Review
- Eph receptors and ephrins in cancer progression.Nature reviews. Cancer · 2024Review
- Time-resolved live-cell spectroscopy reveals EphA2 multimeric assembly.Science (New York, N.Y.) · 2023Article
- Single-cell profiling reveals a potent role of quercetin in promoting hair regeneration.Protein & cell · 2023Article
- Progranulin Oncogenic Network in Solid Tumors.Cancers · 2023Review
- The role of EphA2 in ADAM17- and ionizing radiation-enhanced lung cancer cell migration.Frontiers in oncology · 2023Article
- Complexity of progranulin mechanisms of action in mesothelioma.Journal of experimental & clinical cancer research : CR · 2022Article
- Hunting for Novel Routes in Anticancer Drug Discovery: Peptides against Sam-Sam Interactions.International journal of molecular sciences · 2022Review
- Phosphorylation of guanosine monophosphate reductase triggers a GTP-dependent switch from pro- to anti-oncogenic function of EPHA4.Cell chemical biology · 2022Article
- Review
- Regulation of the EphA2 receptor intracellular region by phosphomimetic negative charges in the kinase-SAM linker.Nature communications · 2021Article
- Nuclear-capture of endosomes depletes nuclear G-actin to promote SRF/MRTF activation and cancer cell invasion.Nature communications · 2021Article
- Review
Corrections and comments
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Authors and funding
10 authors at 3 institutions in 2 countries.
Funding
Abstract
Acquired BRAF/MAPK/extracellular signal‒regulated kinase inhibitor resistance in melanoma results in a new transcriptional state associated with an increased risk of metastasis. In this study, we identified noncanonical ephrin receptor (Eph) 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 noncanonical EphA2-S897E in melanoma cells led to a mesenchymal-to-amoeboid transition driven by Cdc42 activation. The induction of mesenchymal-to-amoeboid transition 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 after tail-vain injection. Analysis of BRAF inhibitor‒sensitive and ‒resistant melanoma cells demonstrated resistance to be associated with a mesenchymal-to-amoeboid transition switch, upregulation of Cdc42 activity, increased invasion, and transendothelial migration. The drug-resistant metastatic state was dependent on histone deacetylase 8 activity. Silencing of histone deacetylase 8 led to the inhibition of EphA2 and protein kinase B 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 noncanonical EphA2 signaling, leading to increased melanoma-endothelial cell interactions and enhanced tumor dissemination.
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Registered trials
Read under generation 80e0d062 · epoch 390. Bibliography from PubMed, PubMed Central and OpenAlex; grants from NIH RePORTER; trial links from ClinicalTrials.gov; estimates, votes and beliefs from the OpenQuestion graph.