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Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation

Oncogene volume 41, pages 2571–2586 (2022)Cite this article

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Abstract

Combined therapy with anti-BRAF plus anti-MEK is currently used as first-line treatment of patients with metastatic melanomas harboring the somatic BRAF V600E mutation. However, the main issue with targeted therapy is the acquisition of tumor cell resistance. In a majority of resistant melanoma cells, the resistant process consists in epithelial-to-mesenchymal transition (EMT). This process called phenotype switching makes melanoma cells more invasive. Its signature is characterized by MITF low, AXL high, and actin cytoskeleton reorganization through RhoA activation. In parallel of this phenotype switching phase, the resistant cells exhibit an anarchic cell proliferation due to hyper-activation of the MAP kinase pathway. We show that a majority of human melanoma overexpress discoidin domain receptor 2 (DDR2) after treatment. The same result was found in resistant cell lines presenting phenotype switching compared to the corresponding sensitive cell lines. We demonstrate that DDR2 inhibition induces a decrease in AXL expression and reduces stress fiber formation in resistant melanoma cell lines. In this phenotype switching context, we report that DDR2 control cell and tumor proliferation through the MAP kinase pathway in resistant cells in vitro and in vivo. Therefore, inhibition of DDR2 could be a new and promising strategy for countering this resistance mechanism.

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Fig. 1: Overview of DDR expression in melanoma progression.
Fig. 2: DDR2 regulates AXL expression in resistant invasive melanoma cells.
Fig. 3: DDR2 mediates stress fiber formation in resistant invasive melanoma cells.
Fig. 4: DDRs-associated phenotype switching is involved in MAP kinase pathway activation.
Fig. 5: DDRs are involved in resistant tumor cell proliferation.
Fig. 6: The role of DDRs in a physiological 3D model.
Fig. 7: The role of DDRs in resistant tumor progression in vivo.
Fig. 8: Schematic representation of the distinct roles of DDR1 and DDR2 in vemurafenib-resistant melanoma.

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Acknowledgements

We are grateful to Prof. Longmore for providing us with DDR2 inhibitors. Many thanks to Dr. David Santamaria for giving us advice on this project and for providing us with a list of MAP kinase targets and their associated primers. We are grateful to the Centre de Ressources Biologiques (CRB), Bordeaux, for access to melanoma patient samples.

Funding

This work is supported by Inca (PLBIO Inca, PLBIO15-135), SIRIC BRIO 2, Fondation de France, FRM, équipe labellisée (grant number DEQ20180839586). Margaux Sala is financed by a PhD grant from the French ministère supérieur de l’enseignement et de la recherche.

Author information

Author notes

  1. Elodie Henriet

    Present address: Ewald’s Lab—Department of Cell Biology, John Hopkins University School of Medicine, Baltimore, MD, USA

  2. Aya Abou-Hammoud

    Present address: MFP, UMR 5234, Bordeaux University, 146 Rue Léo Saignat, Bordeaux, F-33076, France

Authors and Affiliations

  1. Inserm, UMR1312, BRIC, BoRdeaux Institute in onCology, 146 Rue Léo Saignat, Bordeaux, F-33076, France

    Margaux Sala, Nathalie Allain, Mélanie Moreau, Arnaud Jabouille, Elodie Henriet, Aya Abou-Hammoud, Arnaud Uguen, Sylvaine Di-Tommaso, Cyril Dourthe, Anne-Aurélie Raymond, Violaine Moreau & Frédéric Saltel

  2. Bordeaux University, 146 Rue Léo Saignat, Bordeaux, F-33076, France

    Margaux Sala, Nathalie Allain, Mélanie Moreau, Arnaud Jabouille, Elodie Henriet, Aya Abou-Hammoud, Sylvaine Di-Tommaso, Cyril Dourthe, Anne-Aurélie Raymond, Violaine Moreau & Frédéric Saltel

  3. Brest University Hospital Center, Department of Pathology, Brest, F-29200, France

    Arnaud Uguen

  4. Oncoprot, UMS 005, Bordeaux, F-33076, France

    Sylvaine Di-Tommaso, Cyril Dourthe, Anne-Aurélie Raymond & Frédéric Saltel

  5. Bordeaux University, Plateforme Protéome, F-33000 Bordeaux, France, F-33000, Bordeaux, France

    Jean-William Dupuy

  6. Bordeaux University Hospital, Dermatology Department, 1 avenue Jean Burguet, F-33000, Bordeaux, France

    Emilie Gerard

  7. Histology Plateforme, UMS 005, Bordeaux, F-33076, France

    Nathalie Dugot-Senant

  8. Common Animal Housing Service, Bordeaux University, Bordeaux, F-33076, France

    Benoit Rousseau

  9. INSERM, UMR1053, BaRITOn, Bordeaux Research in Translational Oncology, Team 3, “Cutaneous Lymphoma Oncogenesis”, 146 Rue Léo Saignat, Bordeaux, F-33076, France

    Jean-Phillipe Merlio, Anne Pham-Ledart & Béatrice Vergier

  10. Bordeaux University Hospital, Tumor Bank and Tumor Biology Laboratory, Avenue de Magellan, Pessac, F-33604, France

    Jean-Phillipe Merlio, Anne Pham-Ledart & Béatrice Vergier

  11. Université Côte d’Azur, INSERM, C3M, 06204, Nice, France

    Sophie Tartare-Deckert

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  1. Margaux Sala
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Contributions

MS, NA, AJ, MM, EH, AAH and AU performed experiments. SDT, JWD, AAR and CD ran proteomic assay. EG, JPM, APL, BV and AU helped with their clinical knowledge and expertise in melanoma. NDS performed the immunohistochemical-labelling studies. BR helped with the xenograft mouse model. STD and VM provided feedback about the experiments. MS and FS contributed to design and interpretation of the experiments and to the writing of the manuscript. FS coordinated the study. All authors have approved the final version of the paper.

Corresponding author

Correspondence to Frédéric Saltel.

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The institutional animal ethics committee of Bordeaux University approved all animal use procedures and all efforts were made to minimize animal suffering.

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Sala, M., Allain, N., Moreau, M. et al. Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation. Oncogene 41, 2571–2586 (2022). https://doi.org/10.1038/s41388-022-02266-1

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