Cancer Cell
Volume 33, Issue 5, 14 May 2018, Pages 890-904.e5
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Article
Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent Oxidative Stress

https://doi.org/10.1016/j.ccell.2018.03.017Get rights and content
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Highlights

  • Melanoma differentiation involves four progressive stepwise states

  • Differentiation is two-dimensional with an intermediate neural crest signature

  • Melanoma dedifferentiation increases sensitivity to ferroptosis

  • Co-targeting ferroptosis can block the dedifferentiation resistance escape route

Summary

Malignant transformation can result in melanoma cells that resemble different stages of their embryonic development. Our gene expression analysis of human melanoma cell lines and patient tumors revealed that melanoma follows a two-dimensional differentiation trajectory that can be subclassified into four progressive subtypes. This differentiation model is associated with subtype-specific sensitivity to iron-dependent oxidative stress and cell death known as ferroptosis. Receptor tyrosine kinase-mediated resistance to mitogen-activated protein kinase targeted therapies and activation of the inflammatory signaling associated with immune therapy involves transitions along this differentiation trajectory, which lead to increased sensitivity to ferroptosis. Therefore, ferroptosis-inducing drugs present an orthogonal therapeutic approach to target the differentiation plasticity of melanoma cells to increase the efficacy of targeted and immune therapies.

Keywords

ferroptosis
melanoma
differentiation
combination therapy
pharmacogenomics
systems biology
kinase inhibitor therapy
immunotherapy

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