Otto Warburg described tumour cells as displaying enhanced aerobic glycolysis whilst maintaining defective oxidative phosphorylation (OXPHOS) for energy production almost 100 years ago [1, 2]. Since then, the ‘Warburg effect’ has been widely accepted as a key feature of rapidly proliferating cancer cells [3,4,5]. What is not clear is how early “Warburg metabolism” initiates in cancer and whether changes in energy metabolism might influence tumour progression ab initio. We set out to investigate energy metabolism in the HRAS^G12V driven preneoplastic cell (PNC) at inception, in a zebrafish skin PNC model. We find that, within 24 h of HRAS^G12V induction, PNCs upregulate glycolysis and blocking glycolysis reduces PNC proliferation, whilst increasing available glucose enhances PNC proliferation and reduces apoptosis. Impaired OXPHOS accompanies enhanced glycolysis in PNCs, and a mild complex I inhibitor, metformin, selectively suppresses expansion of PNCs. Enhanced mitochondrial fragmentation might be underlining impaired OXPHOS and blocking mitochondrial fragmentation triggers PNC apoptosis. Our data indicate that altered energy metabolism is one of the earliest events upon oncogene activation in somatic cells, which allows a targeted and effective PNC elimination.

大约 100 年前，Otto Warburg 将肿瘤细胞描述为表现出增强的有氧糖酵解，同时维持有缺陷的氧化磷酸化 (OXPHOS) 以产生能量 [1, 2]。从那时起，“瓦尔堡效应”被广泛认为是癌细胞快速增殖的一个关键特征[3,4,5]。目前尚不清楚的是，“Warburg 代谢”在癌症中是如何早期启动的，以及能量代谢的变化是否可能从头开始影响肿瘤的进展。我们着手在斑马鱼皮肤 PNC 模型中研究 HRAS ^{G12V驱动的癌前细胞 (PNC) 的能量代谢。}我们发现，在 HRAS ^G12V诱导后 24 小时内，PNC 上调糖酵解并阻断糖酵解可减少 PNC 增殖，同时增加可用葡萄糖可增强 PNC 增殖并减少细胞凋亡。OXPHOS 受损会伴随 PNC 中糖酵解的增强，而温和的复合物 I 抑制剂二甲双胍可选择性抑制 PNC 的扩张。增强的线粒体碎片可能会导致 OXPHOS 受损，而阻断线粒体碎片则会触发 PNC 细胞凋亡。我们的数据表明，能量代谢的改变是体细胞中癌基因激活后最早发生的事件之一，从而可以有针对性地有效消除 PNC。