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Lineage-Restricted Regulation of SCD and Fatty Acid Saturation by MITF Controls Melanoma Phenotypic Plasticity.
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-13 , DOI: 10.1016/j.molcel.2019.10.014 Yurena Vivas-García 1 , Paola Falletta 1 , Jana Liebing 2 , Pakavarin Louphrasitthiphol 1 , Yongmei Feng 3 , Jagat Chauhan 1 , David A Scott 3 , Nicole Glodde 2 , Ana Chocarro-Calvo 4 , Sarah Bonham 5 , Andrei L Osterman 3 , Roman Fischer 5 , Ze'ev Ronai 3 , Custodia García-Jiménez 6 , Michael Hölzel 2 , Colin R Goding 1
Molecular Cell ( IF 14.5 ) Pub Date : 2019-11-13 , DOI: 10.1016/j.molcel.2019.10.014 Yurena Vivas-García 1 , Paola Falletta 1 , Jana Liebing 2 , Pakavarin Louphrasitthiphol 1 , Yongmei Feng 3 , Jagat Chauhan 1 , David A Scott 3 , Nicole Glodde 2 , Ana Chocarro-Calvo 4 , Sarah Bonham 5 , Andrei L Osterman 3 , Roman Fischer 5 , Ze'ev Ronai 3 , Custodia García-Jiménez 6 , Michael Hölzel 2 , Colin R Goding 1
Affiliation
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Phenotypic and metabolic heterogeneity within tumors is a major barrier to effective cancer therapy. How metabolism is implicated in specific phenotypes and whether lineage-restricted mechanisms control key metabolic vulnerabilities remain poorly understood. In melanoma, downregulation of the lineage addiction oncogene microphthalmia-associated transcription factor (MITF) is a hallmark of the proliferative-to-invasive phenotype switch, although 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 signaling, and an ATF4-mediated feedback loop that maintains de-differentiation. Our results reveal that MITF is a lineage-specific regulator of metabolic reprogramming, whereby fatty acid composition is a driver of melanoma phenotype switching, and highlight that cell phenotype dictates the response to drugs targeting lipid metabolism.
中文翻译：
MITF对SCD和脂肪酸饱和度的谱系限制调节可控制黑色素瘤表型可塑性。
肿瘤内的表型和代谢异质性是有效癌症治疗的主要障碍。如何代谢涉及特定的表型，以及谱系限制机制是否控制关键的代谢脆弱性仍然知之甚少。在黑色素瘤中，尽管MITF如何促进增殖和抑制侵袭，但对成瘾成因癌基因小眼症相关转录因子（MITF）的下调是增生-侵袭表型转换的标志。在这里，我们显示MITF是关键脂肪生成酶硬脂酰辅酶A去饱和酶（SCD）的谱系限制激活剂，并且SCD是MITFHigh黑色素瘤细胞增殖所必需的。相比之下，MITFLow细胞对SCD抑制不敏感。值得注意的是，MITF-SCD轴可抑制转移，炎症信号传导，以及由ATF4介导的反馈回路，可保持去分化。我们的结果表明，MITF是代谢重编程的谱系特异性调节剂，其中脂肪酸组成是黑色素瘤表型转换的驱动力，并强调了细胞表型决定了对靶向脂质代谢的药物的反应。
更新日期：2019-11-13
中文翻译：
MITF对SCD和脂肪酸饱和度的谱系限制调节可控制黑色素瘤表型可塑性。
肿瘤内的表型和代谢异质性是有效癌症治疗的主要障碍。如何代谢涉及特定的表型，以及谱系限制机制是否控制关键的代谢脆弱性仍然知之甚少。在黑色素瘤中，尽管MITF如何促进增殖和抑制侵袭，但对成瘾成因癌基因小眼症相关转录因子（MITF）的下调是增生-侵袭表型转换的标志。在这里，我们显示MITF是关键脂肪生成酶硬脂酰辅酶A去饱和酶（SCD）的谱系限制激活剂，并且SCD是MITFHigh黑色素瘤细胞增殖所必需的。相比之下，MITFLow细胞对SCD抑制不敏感。值得注意的是，MITF-SCD轴可抑制转移，炎症信号传导，以及由ATF4介导的反馈回路，可保持去分化。我们的结果表明，MITF是代谢重编程的谱系特异性调节剂，其中脂肪酸组成是黑色素瘤表型转换的驱动力，并强调了细胞表型决定了对靶向脂质代谢的药物的反应。
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