Clear cell renal cell carcinoma (ccRCC), the most common type of kidney cancer, is largely incurable in the metastatic setting. ccRCC is characterized by excessive lipid accumulation that protects cells from stress and promotes tumor growth, suggesting that the underlying regulators of lipid storage could represent potential therapeutic targets. Here, we evaluated the regulatory roles of GPR1 and CMKLR1, two G-protein coupled receptors of the pro-tumorigenic adipokine chemerin that is involved in ccRCC lipid metabolism. Both genetic and pharmacological suppression of either receptor suppressed lipid formation and induced multiple forms of cell death, including apoptosis, ferroptosis and autophagy, significantly impeding ccRCC growth in cell lines and patient derived xenograft (PDX) models. Comprehensive lipidomic and transcriptomic profiling of receptor competent and depleted cells revealed overlapping and unique signaling of the receptors granting control over triglyceride synthesis, ceramide production, and fatty acid saturation and class production. Mechanistically, the receptors both enforced suppression of the triglyceride lipase ATGL but also demonstrated distinct functions, such as the unique ability of CMKLR1 to control lipid uptake through regulation of SREBP1c and the CD36 scavenger receptor. Treating PDX models with the CMKLR1-targeting small molecule α-NETA led to a dramatic reduction of tumor growth, lipid storage, and clear cell morphology. Together, these findings provide mechanistic insight into lipid regulation in ccRCC and identify a targetable axis at the core of the histological definition of this tumor that could be exploited therapeutically.

中文翻译：

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GPR1 和 CMKLR1 控制脂质代谢以支持透明细胞肾细胞癌的发展

透明细胞肾细胞癌（ccRCC）是最常见的肾癌类型，在转移情况下基本上无法治愈。 ccRCC 的特点是过度的脂质积累，可以保护细胞免受压力并促进肿瘤生长，这表明脂质储存的潜在调节因子可能代表潜在的治疗靶点。在这里，我们评估了 GPR1 和 CMKLR1 的调节作用，这两种 G 蛋白偶联受体是参与 ccRCC 脂质代谢的促肿瘤脂肪因子凯莫瑞。任一受体的遗传和药理学抑制都会抑制脂质形成并诱导多种形式的细胞死亡，包括细胞凋亡、铁死亡和自噬，显着阻碍细胞系和患者来源的异种移植（PDX）模型中的 ccRCC 生长。对受体感受态和耗尽细胞的全面脂质组学和转录组学分析揭示了受体的重叠和独特信号传导，从而控制甘油三酯合成、神经酰胺产生以及脂肪酸饱和和类产生。从机制上讲，这些受体不仅强制抑制甘油三酯脂肪酶 ATGL，而且还表现出独特的功能，例如 CMKLR1 通过调节 SREBP1c 和 CD36 清道夫受体来控制脂质摄取的独特能力。使用 CMKLR1 靶向小分子 α-NETA 处理 PDX 模型可显着减少肿瘤生长、脂质储存和透明细胞形态。总之，这些发现提供了对 ccRCC 脂质调节的机制见解，并确定了该肿瘤组织学定义核心的可用于治疗的可靶向轴。