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MCU controls melanoma progression through a redox-controlled phenotype switch

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Wittek,  Anna       
Research Group of Mitochondrial Structure and Dynamics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Lange,  Felix
Research Group of Mitochondrial Structure and Dynamics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Urlaub,  Henning
Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Lenz,  Christof
Research Group of Bioanalytical Mass Spectrometry, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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Jakobs,  Stefan       
Department of NanoBiophotonics, Max Planck Institute for Multidisciplinary Sciences, Max Planck Society;

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MCU controls_1.pdf
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Citation

Stejerean-Todoran, I., Zimmermann, K., Gibhardt, C. S., Vultur, A., Ickes, C., Shannan, B., et al. (2022). MCU controls melanoma progression through a redox-controlled phenotype switch. EMBO Reports, 23: e54746. doi:10.15252/embr.202254746.


Cite as: https://hdl.handle.net/21.11116/0000-000C-34E4-8
Abstract
Melanoma is the deadliest of skin cancers and has a high tendency to metastasize to distant organs. Calcium and metabolic signals contribute to melanoma invasiveness; however, the underlying molecular details are elusive. The MCU complex is a major route for calcium into the mitochondrial matrix but whether MCU affects melanoma pathobiology was not understood. Here, we show that MCUA expression correlates with melanoma patient survival and is decreased in BRAF kinase inhibitor-resistant melanomas. Knockdown (KD) of MCUA suppresses melanoma cell growth and stimulates migration and invasion. In melanoma xenografts, MCUA_KD reduces tumor volumes but promotes lung metastases. Proteomic analyses and protein microarrays identify pathways that link MCUA and melanoma cell phenotype and suggest a major role for redox regulation. Antioxidants enhance melanoma cell migration, while prooxidants diminish the MCUA_KD-induced invasive phenotype. Furthermore, MCUA_KD increases melanoma cell resistance to immunotherapies and ferroptosis. Collectively, we demonstrate that MCUA controls melanoma aggressive behavior and therapeutic sensitivity. Manipulations of mitochondrial calcium and redox homeostasis, in combination with current therapies, should be considered in treating advanced melanoma.