1. Discoidin Domain Receptor 2 orchestrates melanoma resistance combining phenotype switching and proliferation
- Author
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Margaux Sala, Nathalie Allain, Mélanie Moreau, Arnaud Jabouille, Elodie Henriet, Aya Abou-Hammoud, Arnaud Uguen, Sylvaine Di-Tommaso, Cyril Dourthe, Anne-Aurélie Raymond, Jean-William Dupuy, Emilie Gerard, Nathalie Dugot-Senant, Benoit Rousseau, Jean-Phillipe Merlio, Anne Pham-Ledart, Béatrice Vergier, Sophie Tartare-Deckert, Violaine Moreau, Frédéric Saltel, BoRdeaux Institute in onCology (Inserm U1312 - BRIC), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM), Johns Hopkins University (JHU), Microbiologie Fondamentale et Pathogénicité (MFP), Université Bordeaux Segalen - Bordeaux 2-Centre National de la Recherche Scientifique (CNRS), Hôpital Morvan - CHRU de Brest (CHU - BREST ), TBM-Core [Bordeaux] (CNRS UMS 3427 - INSERM US 005), Université de Bordeaux (UB)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Centre National de la Recherche Scientifique (CNRS), Université de Bordeaux (UB), CHU Bordeaux [Bordeaux], Bordeaux Research In Translational Oncology [Bordeaux] (BaRITOn), Université de Bordeaux (UB)-CHU Bordeaux [Bordeaux]-Institut National de la Santé et de la Recherche Médicale (INSERM), Centre méditerranéen de médecine moléculaire (C3M), Université Nice Sophia Antipolis (1965 - 2019) (UNS), COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-COMUE Université Côte d'Azur (2015-2019) (COMUE UCA)-Institut National de la Santé et de la Recherche Médicale (INSERM)-Université Côte d'Azur (UCA), and TARTARE-DECKERT, Sophie
- Subjects
Proto-Oncogene Proteins B-raf ,MESH: Proto-Oncogene Proteins B-raf ,Cancer Research ,MESH: Cell Line, Tumor ,MESH: Humans ,MESH: Melanoma ,[SDV]Life Sciences [q-bio] ,MESH: Phenotype ,MESH: Drug Resistance, Neoplasm ,[SDV] Life Sciences [q-bio] ,Discoidin Domain Receptor 2 ,Phenotype ,Drug Resistance, Neoplasm ,Cell Line, Tumor ,MESH: Cell Proliferation ,MESH: Discoidin Domain Receptor 2 ,Genetics ,Humans ,MESH: Protein Kinase Inhibitors ,Melanoma ,Protein Kinase Inhibitors ,Molecular Biology ,Cell Proliferation - Abstract
International audience; 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.
- Published
- 2022
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