Department 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.
Department of Medicine, UCLA, Los Angeles, CA 90095, USA.
Cancer Cell. 2018 May 14;33(5):890-904.e5. doi: 10.1016/j.ccell.2018.03.017. Epub 2018 Apr 12.
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.
恶性转化可导致黑素瘤细胞类似于其胚胎发育的不同阶段。我们对人类黑素瘤细胞系和患者肿瘤的基因表达分析表明，黑素瘤遵循二维分化轨迹，可分为四个渐进亚型。这种分化模型与对铁依赖性氧化应激和细胞死亡（称为铁死亡）的亚类特异性敏感性相关。受体酪氨酸激酶介导的对丝裂原激活的蛋白激酶靶向治疗的耐药性和与免疫治疗相关的炎症信号的激活涉及沿着该分化轨迹的转变，这导致对铁死亡的敏感性增加。因此，诱导铁死亡的药物提供了一种正交的治疗方法，以针对黑素瘤细胞的分化可塑性，提高靶向和免疫治疗的疗效。
