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Dual Effects of Melanoma Cell-derived Factors on Bone Marrow Adipocytes Differentiation
Published on: August 23, 2018
Multi-stage Differentiation Defines Melanoma Subtypes with Differential Vulnerability to Drug-Induced Iron-Dependent
Jennifer Tsoi1, Lidia Robert2, Kim Paraiso1
1Department of Molecular and Medical Pharmacology, University of California, Los Angeles (UCLA), 570 Westwood Plaza, Building 114, Los Angeles, CA 90095, USA; Crump Institute for Molecular Imaging, UCLA, Los Angeles, CA 90095, USA.
None:
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.
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