Lineage-restricted regulation of SCD and fatty acid saturation by MITF controls melanoma phenotypic plasticity

Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. Yet how metabolism is implicated in specific phenotypes, and whether lineage-restricted mechanisms control key metabolic vulnerabilities remains poorly understood. In melanoma, down-regulation of the lineage addiction oncogene Microphthalmia-associated Transcription Factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, though how MITF promotes proliferation and suppresses invasion is poorly defined. Here we show that MITF is a lineage restricted activator of the key lipogenic enzyme stearoyl-CoA desaturase (SCD), and that SCD is required for MITFHigh melanoma cell proliferation. By contrast MITFLow cells are insensitive to SCD inhibition. Significantly, the MITF-SCD axis suppresses metastasis, inflammatory signalling, and an ATF4-mediated feedback-loop that maintains dedifferentiation. Our results reveal that MITF is a lineagespecific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype-switching, and highlight that cell phenotype dictates response to drugs targeting lipid metabolism. Overall design: 501mel and IGR37 melanoma cell lines were treated with the indicated siRNA or SCD inhibitors for 48h prior to RNA extraction and sequencing

肿瘤内的表型与代谢异质性是有效癌症治疗的主要障碍。然而，代谢如何参与特定表型的调控，以及谱系限制性机制是否调控关键代谢脆弱性，目前仍不甚明晰。在黑色素瘤中，谱系成瘾癌基因小眼症相关转录因子（Microphthalmia-associated Transcription Factor, MITF）的下调是增殖型向侵袭型表型转换的标志性事件，但MITF如何促进增殖并抑制侵袭的具体机制仍未明确。本研究证实，MITF是关键脂生成酶硬脂酰辅酶A去饱和酶（stearoyl-CoA desaturase, SCD）的谱系限制性激活因子，且SCD对于MITF高表达（MITFHigh）黑色素瘤细胞的增殖不可或缺。与之相反，MITF低表达（MITFLow）细胞对SCD抑制剂不敏感。尤为关键的是，MITF-SCD轴可抑制肿瘤转移、炎症信号通路，以及维持细胞去分化状态的ATF4介导的反馈环路。本研究结果表明，MITF是代谢重编程的谱系特异性调控因子，脂肪酸组成是驱动黑色素瘤表型转换的关键因素，并揭示细胞表型决定了靶向脂质代谢药物的响应效果。整体实验设计：将501mel与IGR37黑色素瘤细胞系用指定的小干扰RNA（small interfering RNA, siRNA）或SCD抑制剂处理48小时，随后提取RNA并进行测序。