Most kidney cancers are metabolically dysfunctional^1,2,3,4, but how this dysfunction affects cancer progression in humans is unknown. We infused ¹³C-labelled nutrients in over 80 patients with kidney cancer during surgical tumour resection. Labelling from [U-¹³C]glucose varies across subtypes, indicating that the kidney environment alone cannot account for all tumour metabolic reprogramming. Compared with the adjacent kidney, clear cell renal cell carcinomas (ccRCCs) display suppressed labelling of tricarboxylic acid (TCA) cycle intermediates in vivo and in ex vivo organotypic cultures, indicating that suppressed labelling is tissue intrinsic. [1,2-¹³C]acetate and [U-¹³C]glutamine infusions in patients, coupled with measurements of respiration in isolated human kidney and tumour mitochondria, reveal lower electron transport chain activity in ccRCCs that contributes to decreased oxidative and enhanced reductive TCA cycle labelling. However, ccRCC metastases unexpectedly have enhanced TCA cycle labelling compared with that of primary ccRCCs, indicating a divergent metabolic program during metastasis in patients. In mice, stimulating respiration or NADH recycling in kidney cancer cells is sufficient to promote metastasis, whereas inhibiting electron transport chain complex I decreases metastasis. These findings in humans and mice indicate that metabolic properties and liabilities evolve during kidney cancer progression, and that mitochondrial function is limiting for metastasis but not growth at the original site.

大多数肾癌存在代谢功能障碍^1,2,3,4 ，但这种功能障碍如何影响人类癌症进展尚不清楚。我们在肿瘤手术切除过程中为 80 多名肾癌患者注射了¹³ C 标记的营养素。 [U- ¹³ C]葡萄糖的标记因亚型而异，表明仅靠肾脏环境无法解释所有肿瘤代谢重编程。与邻近的肾脏相比，透明细胞肾细胞癌（ccRCC）在体内和离体器官型培养物中表现出三羧酸（TCA）循环中间体的抑制标记，表明抑制标记是组织固有的。对患者输注 [1,2- ¹³ C]乙酸盐和 [U- ¹³ C]谷氨酰胺，再加上对分离的人肾和肿瘤线粒体的呼吸测量，揭示了 ccRCC 中较低的电子传递链活性，这有助于减少氧化并增强还原TCA 循环标签。然而，与原发性 ccRCC 相比，ccRCC 转移瘤的 TCA 循环标记出人意料地增强，表明患者在转移过程中存在不同的代谢程序。在小鼠中，刺激肾癌细胞的呼吸或 NADH 循环足以促进转移，而抑制电子传递链复合物 I 则可减少转移。这些在人类和小鼠中的发现表明，代谢特性和负担在肾癌进展过程中发生变化，并且线粒体功能限制了转移，但不限制原位点的生长。