A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis.,Nature Communications

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A GPX4-dependent cancer cell state underlies the clear-cell morphology and confers sensitivity to ferroptosis.
Nature Communications ( IF 14.7 ) Pub Date : 2019-04-08 , DOI: 10.1038/s41467-019-09277-9
Yilong Zou _{1,

2} , Michael J Palte ₁ , Amy A Deik ₁ , Haoxin Li _{1,

2} , John K Eaton ₁ , Wenyu Wang ₁ , Yuen-Yi Tseng ₁ , Rebecca Deasy ₁ , Maria Kost-Alimova ₁ , Vlado Dančík ₁ , Elizaveta S Leshchiner ₁ , Vasanthi S Viswanathan ₁ , Sabina Signoretti ₃ , Toni K Choueiri ₄ , Jesse S Boehm ₁ , Bridget K Wagner ₁ , John G Doench ₁ , Clary B Clish ₁ , Paul A Clemons ₁ , Stuart L Schreiber _{1,

2}

Affiliation

Clear-cell carcinomas (CCCs) are a histological group of highly aggressive malignancies commonly originating in the kidney and ovary. CCCs are distinguished by aberrant lipid and glycogen accumulation and are refractory to a broad range of anti-cancer therapies. Here we identify an intrinsic vulnerability to ferroptosis associated with the unique metabolic state in CCCs. This vulnerability transcends lineage and genetic landscape, and can be exploited by inhibiting glutathione peroxidase 4 (GPX4) with small-molecules. Using CRISPR screening and lipidomic profiling, we identify the hypoxia-inducible factor (HIF) pathway as a driver of this vulnerability. In renal CCCs, HIF-2α selectively enriches polyunsaturated lipids, the rate-limiting substrates for lipid peroxidation, by activating the expression of hypoxia-inducible, lipid droplet-associated protein (HILPDA). Our study suggests targeting GPX4 as a therapeutic opportunity in CCCs, and highlights that therapeutic approaches can be identified on the basis of cell states manifested by morphological and metabolic features in hard-to-treat cancers.

中文翻译：

GPX4 依赖性癌细胞状态是透明细胞形态的基础，并赋予对铁死亡的敏感性。

透明细胞癌（CCC）是一组高度侵袭性的恶性肿瘤，通常起源于肾脏和卵巢。 CCC 的特点是异常的脂质和糖原积累，并且对多种抗癌疗法都无效。在这里，我们发现了与 CCC 独特的代谢状态相关的铁死亡的内在脆弱性。这种漏洞超越了谱系和遗传景观，可以通过用小分子抑制谷胱甘肽过氧化物酶 4 (GPX4) 来利用。使用 CRISPR 筛选和脂质组学分析，我们确定缺氧诱导因子 (HIF) 途径是该漏洞的驱动因素。在肾 CCC 中，HIF-2α 通过激活缺氧诱导脂滴相关蛋白 (HILPDA) 的表达，选择性地富集多不饱和脂质（脂质过氧化的限速底物）。我们的研究建议将 GPX4 作为 CCC 的治疗机会，并强调可以根据难治性癌症的形态和代谢特征所表现的细胞状态来确定治疗方法。

更新日期：2019-04-08

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