Abstract
Receptor tyrosine kinase-like orphan receptor 2 (ROR2) is a protein with important functions during embryogenesis that is dysregulated in human cancer. An intriguing feature of this receptor is that it plays opposite roles in different tumor types either promoting or inhibiting tumor progression. Understanding the complex role of this receptor requires a more profound exploration of both the altered biological and molecular mechanisms. Here, we describe that ROR2 promotes Epithelial–Mesenchymal Transition (EMT) by inducing cadherin switch and the upregulation of the transcription factors ZEB1, Twist, Slug, Snail, and HIF1A, together with a mesenchymal phenotype and increased migration. We show that ROR2 activates both p38 and ERK mitogen-activated protein kinase pathways independently of Wnt5a. Further, we demonstrated that the upregulation of EMT-related proteins depends on the hyperactivation of the ERK pathway far above the typical high constitutive activity observed in melanoma. In addition, ROR2 also promoted ERK phosphorylation, EMT, invasion, and necrosis in xenotransplanted mice. ROR2 also associates with EMT in tumor samples from melanoma patients where analysis of large cohorts revealed that increased ROR2 levels are linked to EMT signatures. This important role of ROR2 translates into melanoma patientʹ s prognosis since elevated ROR2 levels reduced overall survival and distant metastasis-free survival of patients with lymph node metastasis. In sum, these results demonstrate that ROR2 contributes to melanoma progression by inducing EMT and necrosis and can be an attractive therapeutic target for melanoma.
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Data sharing is not applicable to this article as no datasets were generated during the current study.
Abbreviations
- EMT:
-
Epithelial-to-mesenchymal transition
- FFPE:
-
Formalin-fixed paraffin embedded
- MSS:
-
Melanoma-specific survival
- LMC:
-
Leeds melanoma cohort
- GEO:
-
Gene expression omnibus
- DEG:
-
Differentially expressed genes
- PLX:
-
PLX-4032
- LNM:
-
Lymph node metastasis
- dMFS:
-
Distant metastasis-free survival
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Acknowledgements
We thank Dr. Claudia Cocca (Facultad de Farmacia y Bioquímica, UBA) for providing the E-cadherin antibody. We thank Miss Alejandra Fisz for administrative assistance and Engr. Alberto Varela and his crew for technical assistance. We thank Sara Correa and Diego Vazquez for expert assistance with histotechniques.
Funding
This research was supported by grants BID-PICT-2015-513 and BID-PICT-2011-605 from the Agencia Nacional de Promoción Científica y Tecnológica (ANPCyT) and grants from Fundación Científica Felipe Fiorellino. Consejo Nacional de Investigaciones Científicas y Técnicas (CONICET) provided fellowships to MVC, GB, MBV, and MJQ. The Leeds Melanoma Cohort was built using Grants CR UK C588/A19167, C8216/A6129 and C588/A10721 and NIH CA83115.
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MVC performed most of the experiments and was responsible for analysis and visualization of the data. GAB contributed to the experiments and the methodology. MBV and PM helped with the methodology. JN and JNB conducted the analysis of ROR2 expression in the LMC. EI contributed with the analysis of IHC data. MJQ contributed to the experiments. PLB was responsible for conceptualization, funding acquisition and project administration. He was also responsible for writing and editing the manuscript. All the authors provided feedback on the report.
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Castro, M.V., Barbero, G.A., Máscolo, P. et al. ROR2 promotes epithelial-mesenchymal transition by hyperactivating ERK in melanoma. J. Cell Commun. Signal. 17, 75–88 (2023). https://doi.org/10.1007/s12079-022-00683-1
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DOI: https://doi.org/10.1007/s12079-022-00683-1