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Updated: Apr 27, 2026
A Robust Discovery Platform for the Identification of Novel Mediators of Melanoma Metastasis
Published on: March 8, 2022
Targeting SRPK1 to control VEGF-mediated tumour angiogenesis in metastatic melanoma
M V Gammons1, R Lucas1, R Dean1
1Microvascular Research Laboratories, School of Physiology and Pharmacology, Preclinical Veterinary Sciences Building, University of Bristol, Southwell Street, Bristol BS2 8EJ, UK.
Background:
Current therapies for metastatic melanoma are targeted either at cancer mutations driving growth (e.g., vemurafenib) or immune-based therapies (e.g., ipilimumab). Tumour progression also requires angiogenesis, which is regulated by VEGF-A, itself alternatively spliced to form two families of isoforms, pro- and anti-angiogenic. Metastatic melanoma is associated with a splicing switch to pro-angiogenic VEGF-A, previously shown to be regulated by SRSF1 phosphorylation by SRPK1. Here, we show a novel approach to preventing angiogenesis-targeting splicing factor kinases that are highly expressed in melanomas.
Methods:
We used RT-PCR, western blotting and immunohistochemistry to investigate SRPK1, SRSF1 and VEGF expression in tumour cells, and in vivo xenograft assays to investigate SRPK1 knockdown and inhibition in vivo.
Results:
In both uveal and cutaneous melanoma cell lines, SRPK1 was highly expressed, and inhibition of SRPK1 by knockdown or with pharmacological inhibitors reduced pro-angiogenic VEGF expression maintaining the production of anti-angiogenic VEGF isoforms. Both pharmacological SRPK1 inhibitors and SRPK1 knockdown reduced growth of human melanomas in vivo, but neither affected cell proliferation in vitro.
Conclusions:
These results suggest that selective blocking of pro-angiogenic isoforms by inhibiting splice-site selection with SRPK1 inhibitors reduces melanoma growth. SRPK1 inhibitors may be used as therapeutic agents.
Insights
Targeting splicing factor kinases like SRPK1 offers a new strategy for metastatic melanoma. Inhibiting SRPK1 reduces pro-angiogenic VEGF, thereby decreasing melanoma growth without affecting normal cell proliferation.
Area of Science:
- Molecular Biology
- Oncology
- Biochemistry
Background:
- Metastatic melanoma treatments target cancer mutations or immune responses.
- Tumor growth involves angiogenesis regulated by vascular endothelial growth factor A (VEGF-A) isoforms.
- Melanoma exhibits a splicing switch favoring pro-angiogenic VEGF-A, influenced by SRSF1 phosphorylation by SRPK1.
Purpose of the Study:
- To investigate a novel therapeutic strategy targeting splicing factor kinases in melanoma.
- To evaluate the role of SRPK1 in regulating VEGF-A splicing and melanoma progression.
- To assess the efficacy of SRPK1 inhibition in reducing melanoma growth.
Main Methods:
- RT-PCR, western blotting, and immunohistochemistry were used to analyze SRPK1, SRSF1, and VEGF expression.
- In vivo xenograft assays were performed to study the effects of SRPK1 knockdown and inhibition.
- Pharmacological SRPK1 inhibitors were employed in both in vitro and in vivo experiments.
Main Results:
- SRPK1 was highly expressed in both uveal and cutaneous melanoma cell lines.
- SRPK1 inhibition (via knockdown or inhibitors) reduced pro-angiogenic VEGF expression and maintained anti-angiogenic isoforms.
- Pharmacological SRPK1 inhibitors and SRPK1 knockdown significantly reduced melanoma tumor growth in vivo, but not in vitro proliferation.
Conclusions:
- Selective blockade of pro-angiogenic VEGF isoforms by inhibiting SRPK1 reduces melanoma growth.
- SRPK1 inhibitors represent a potential therapeutic strategy for metastatic melanoma.
- Targeting splice-site selection via SRPK1 inhibition offers a novel approach to melanoma treatment.
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