ArticleJournal of experimental & clinical cancer research : CR2022
SEMA6A/RhoA/YAP axis mediates tumor-stroma interactions and prevents response to dual BRAF/MEK inhibition in BRAF-mutant melanoma.
Article in Journal of experimental & clinical cancer research : CR, 2022. The graph could read no effect estimate from its abstract, so it casts no vote on the map. Cited by 20 papers.
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Who cites it
20 citing papers in PubMed, 25 citations in OpenAlex.
- Role of semaphorin 4f in cardiac fibroblasts to regulate matrix production through actin remodeling and YAP/TAZ activation.Apoptosis : an international journal on programmed cell death · 2026Article
- Rho GTPases in cancer resistance: mechanisms, vulnerabilities, and therapeutic opportunities.Biochemical Society transactions · 2026Review
- The YAP1 and EPHA3 receptor tyrosine kinase axis regulates cellular plasticity and treatment response.Cellular signalling · 2026Article
- RHOA at the intersection of inflammation-driven and sporadic colorectal cancer.Frontiers in immunology · 2026Review
- Genetic Insight into Expression-Defined Melanoma Subtypes and Network Mechanisms: An in Silico Study.Genes · 2025Article
- Polycystin-1 Mutant Alters Mechanotransduction in Response to Collagen and Extracellular Matrix Stiffness via Daam1-Dependent Microfilament Remodeling.Advanced science (Weinheim, Baden-Wurttemberg, Germany) · 2025Article
- Phenotype switching in highly invasive resistant to vemurafenib and cobimetinib melanoma cells.Cell communication and signaling : CCS · 2025Article
- Genome-wide association study of Fuchs' endothelial corneal dystrophy in the German population.Human genetics · 2025Article
- Long noncoding RNA semaphorin 6A-antisense RNA 1 reduces hepatocellular carcinoma by promoting semaphorin 6A mRNA degradation.World journal of gastroenterology · 2025Article
- SEMA6A overexpression inhibited tumor growth and metastasis in colorectal cancer.Brazilian journal of medical and biological research = Revista brasileira de pesquisas medicas e biologica · 2025Article
- Off-targets of BRAF inhibitors disrupt endothelial signaling and vascular barrier function.Life science alliance · 2024Article
- Pitavastatin sensitizes the EGFR-TKI associated resistance in lung cancer by inhibiting YAP/AKT/BAD-BCL-2 pathway.Cancer cell international · 2024Article
- The MITF/mir-579-3p regulatory axis dictates BRAF-mutated melanoma cell fate in response to MAPK inhibitors.Cell death & disease · 2024Article
- Comprehensive analysis of necroptotic patterns and associated immune landscapes in individualized treatment of skin cutaneous melanoma.Scientific reports · 2023Article
- Upregulated expression of miR-4443 and miR-4488 in drug resistant melanomas promotes migratory and invasive phenotypes through downregulation of intermediate filament nestin.Journal of experimental & clinical cancer research : CR · 2023Article
- Semaphorin 6 Family-An Important Yet Overlooked Group of Signaling Proteins Involved in Cancerogenesis.Cancers · 2023Review
- JTE-013 Alleviates Pulmonary Fibrosis by Affecting the RhoA/YAP Pathway and Mitochondrial Fusion/Fission.Pharmaceuticals (Basel, Switzerland) · 2023Article
- Review
- Extracellular Vesicles-Based Cell-Cell Communication in Melanoma: New Perspectives in Diagnostics and Therapy.International journal of molecular sciences · 2023Review
- The role of lncRNAs in the tumor microenvironment and immunotherapy of melanoma.Frontiers in immunology · 2022Review
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Authors and funding
20 authors at 4 institutions in 2 countries.
Funding
Abstract
backgroundDespite the promise of dual BRAF/MEK inhibition as a therapy for BRAF-mutant (BRAF-mut) melanoma, heterogeneous responses have been observed in patients, thus predictors of benefit from therapy are needed. We have previously identified semaphorin 6A (SEMA6A) as a BRAF-mut-associated protein involved in actin cytoskeleton remodeling. The purpose of the present study is to dissect the role of SEMA6A in the biology of BRAF-mut melanoma, and to explore its predictive potential towards dual BRAF/MEK inhibition.
methodsSEMA6A expression was assessed by immunohistochemistry in melanoma cohort RECI1 (N = 112) and its prognostic potential was investigated in BRAF-mut melanoma patients from DFCI and TCGA datasets (N = 258). The molecular mechanisms regulated by SEMA6A to sustain tumor aggressiveness and targeted therapy resistance were investigated in vitro by using BRAF-mut and BRAF-wt melanoma cell lines, an inducible SEMA6A silencing cell model and a microenvironment-mimicking fibroblasts-coculturing model. Finally, SEMA6A prediction of benefit from dual BRAF/MEK inhibition was investigated in melanoma cohort RECI2 (N = 14).
resultsOur results indicate higher protein expression of SEMA6A in BRAF-mut compared with BRAF-wt melanoma patients and show that SEMA6A is a prognostic indicator in BRAF-mut melanoma from TCGA and DFCI patients cohorts. In BRAF-mut melanoma cells, SEMA6A coordinates actin cytoskeleton remodeling by the RhoA-dependent activation of YAP and dual BRAF/MEK inhibition by dabrafenib+trametinib induces SEMA6A/RhoA/YAP axis. In microenvironment-mimicking co-culture condition, fibroblasts confer to melanoma cells a proliferative stimulus and protect them from targeted therapies, whereas SEMA6A depletion rescues the efficacy of dual BRAF/MEK inhibition. Finally, in BRAF-mut melanoma patients treated with dabrafenib+trametinib, high SEMA6A predicts shorter recurrence-free interval.
conclusionsOverall, our results indicate that SEMA6A contributes to microenvironment-coordinated evasion of melanoma cells from dual BRAF/MEK inhibition and it might be a good candidate predictor of short-term benefit from dual BRAF/MEK inhibition.
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