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WNT5A-ROR2 axis mediates VEGF dependence of BRAF mutant melanoma
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Coupe, Nicholas, Guo, Lina, Bridges, Esther, Campo, Leticia, Espinosa, Olivia, Colling, Richard, Marshall, Andrea, Nandakumar, Ashwin, van Stiphout, Ruud, Buffa, Francesca M., Corrie, Pippa G., Middleton, Mark R. and Macaulay, Valentine M. (2023) WNT5A-ROR2 axis mediates VEGF dependence of BRAF mutant melanoma. Cellular oncology, 46 . 391-407 . doi:10.1007/s13402-022-00757-7 ISSN 2211-3436.
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WRAP-WNT5A-ROR2-axis-mediates-VEGF-dependence-of-BRAF-mutant-melanoma-Marshall-2022.pdf - Published Version - Requires a PDF viewer. Available under License Creative Commons Attribution 4.0. Download (2249Kb) | Preview |
Official URL: https://doi.org/10.1007/s13402-022-00757-7
Abstract
Purpose
Despite recent advances, approximately 50% of patient with metastatic melanoma eventually succumb to the disease. Patients with melanomas harboring a BRAF mutation (BRAFMut) have a worse prognosis than those with wildtype (BRAFWT) tumors. Unexpectedly, interim AVAST-M Phase III trial data reported benefit from adjuvant anti-VEGF bevacizumab only in the BRAFMut group. We sought to find mechanisms underpinning this sensitivity.
Methods
We investigated this finding in vitro and in vivo using melanoma cell lines and clones generated by BRAFV600E knock-in on a BRAFWT background.
Results
Compared with BRAFWT cells, isogenic BRAFV600E clones secreted more VEGF and exhibited accelerated growth rates as spheroids and xenografts, which were more vascular and proliferative. Recapitulating AVAST-M findings, bevacizumab affected only BRAFV600E xenografts, inducing significant tumor growth delay, reduced vascularity and increased necrosis. We identified 814 differentially expressed genes in isogenic BRAFV600E/BRAFWT clones. Of 61 genes concordantly deregulated in clinical melanomas ROR2 was one of the most upregulated by BRAFV600E. ROR2 was shown to be RAF-MEK regulated in BRAFV600E cells and its depletion suppressed VEGF secretion down to BRAFWT levels. The ROR2 ligand WNT5A was also overexpressed in BRAFMut melanomas, and in ROR2-overexpressing BRAFV600E cells MEK inhibition downregulated WNT5A and VEGF secretion.
Conclusions
These data implicate WNT5A-ROR2 in VEGF secretion, vascularity, adverse outcomes and bevacizumab sensitivity of BRAFMut melanomas, suggesting that this axis has potential therapeutic relevance.
| Item Type: | Journal Article | ||||||||||||||||||
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| Subjects: | R Medicine > RC Internal medicine R Medicine > RS Pharmacy and materia medica |
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| Divisions: | Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School > Clinical Trials Unit Faculty of Science, Engineering and Medicine > Medicine > Warwick Medical School |
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| SWORD Depositor: | Library Publications Router | ||||||||||||||||||
| Library of Congress Subject Headings (LCSH): | Melanoma , Melanoma -- Treatment, Bevacizumab | ||||||||||||||||||
| Journal or Publication Title: | Cellular oncology | ||||||||||||||||||
| Publisher: | Springer | ||||||||||||||||||
| ISSN: | 2211-3436 | ||||||||||||||||||
| Official Date: | April 2023 | ||||||||||||||||||
| Dates: |
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| Volume: | 46 | ||||||||||||||||||
| Number of Pages: | 17 | ||||||||||||||||||
| Page Range: | 391-407 | ||||||||||||||||||
| DOI: | 10.1007/s13402-022-00757-7 | ||||||||||||||||||
| Status: | Peer Reviewed | ||||||||||||||||||
| Publication Status: | Published | ||||||||||||||||||
| Access rights to Published version: | Open Access (Creative Commons) | ||||||||||||||||||
| Date of first compliant deposit: | 16 January 2023 | ||||||||||||||||||
| Date of first compliant Open Access: | 16 January 2023 | ||||||||||||||||||
| RIOXX Funder/Project Grant: |
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