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MNK1 signaling induces an ANGPTL4-mediated gene signature to drive melanoma progression

Oncogene volume 39, pages 3650–3665 (2020)Cite this article

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Abstract

The BRAFV600E mutation occurs in more than 50% of cutaneous melanomas, and results in the constitutive activation of the mitogen-activated protein kinases (MAPK) pathway. MAP kinase-interacting serine/threonine-protein kinase 1 and 2 (MNK1/2) are downstream effectors of the activated MAPK pathway, and important molecular targets in invasive and metastatic cancer. Despite the well-known role of MNK1 in regulating mRNA translation, little is known concerning the impact of its aberrant activation on gene transcription. Here, we show that changes in the activity, or abundance, of MNK1 result in changes in the expression of pro-oncogenic and pro-invasive genes. Among the MNK1-upregulated genes, we identify Angiopoietin-like 4 (ANGPTL4), which in turn promotes an invasive phenotype via its ability to induce the expression of matrix metalloproteinases (MMPs). Using a pharmacologic inhibitor of MNK1/2, SEL201, we demonstrate that BRAFV600E-mutated cutaneous melanoma cells are reliant on MNK1/2 for invasion and lung metastasis.

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Fig. 1: MNK1 mediates transcription of downstream targets involved in tumor progression.
Fig. 2: MNK1 promotes melanoma invasion, metastasis and proliferation.
Fig. 3: MNK1 regulates expression of pro-invasive genes in melanoma via the master regulator, ANGPTL4.
Fig. 4: SEL201 treatment decreases invasion in mouse and human melanoma models.
Fig. 5: MNK1-mediated increase in ANGPTL4 through PPAR activation.
Fig. 6: Clinical relevance of MNK1 in melanoma progression.

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Acknowledgements

This research is funded by the Canadian Institutes for Health Research (grants MOP-142281 PJT-156269 to WHM and SVDR, and grant PJT-162260 to SVDR) and the Canadian Cancer Society (grant 703811 WHM and SVDR). The research was further supported by the Rossy Cancer Network. Development of MNK1/2 inhibitors by Selvita S.A. has been co-financed by the National Centre for Research and Development, INNOTECH Program (INNOTECH-K1/HI1/I6/157438/NCBR/12). WY was endowed by MICRTP graduate studentships. QG was financed by a Cole Foundation Ph.D. fellowship, McGill Integrated Cancer Research Training Program (MICRTP) graduate studentship and a McGill Faculty of Medicine graduate studentship. FH was sponsored by MICRTP graduate studentships. We thank Shalom Chaim Spira for editing this manuscript.

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  1. These authors contributed equally: William Yang, Elie Khoury, Wilson H. Miller Jr., Sonia Victoria del Rincón

Authors and Affiliations

  1. Division of Experimental Medicine, Faculty of Medicine, McGill University, Montréal, QC, Canada

    William Yang, Elie Khoury, Qianyu Guo, Sathyen A. Prabhu, Fan Huang, Yao Zhan, Michael S. Dahabieh, Wilson H. Miller Jr. & Sonia Victoria del Rincón

  2. Lady Davis Institute, Jewish General Hospital, McGill University, Montréal, QC, Canada

    William Yang, Elie Khoury, Qianyu Guo, Sathyen A. Prabhu, Audrey Emond, Fan Huang, Christophe Gonçalves, Yao Zhan, Dany Plourde, Jessica N. Nichol, Michael S. Dahabieh, Wilson H. Miller Jr. & Sonia Victoria del Rincón

  3. Rossy Cancer Network, McGill University, Montréal, QC, Canada

    Wilson H. Miller Jr.

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Contributions

WY, EK, QG, WHM, and SVDR designed the research. WY, EK, QG, SAP, FH, CG, DP, and YZ performed the experiments and analyzed the data. AE analyzed the RNA-Seq data. WY, EK, QG, FH, JNN, MSD, WHM, and SVDR wrote and edited the paper.

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Correspondence to Wilson H. Miller Jr. or Sonia Victoria del Rincón.

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Yang, W., Khoury, E., Guo, Q. et al. MNK1 signaling induces an ANGPTL4-mediated gene signature to drive melanoma progression. Oncogene 39, 3650–3665 (2020). https://doi.org/10.1038/s41388-020-1240-5

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