Mutant KRAS modulates the metabolic plasticity of cancer cells to confer a growth advantage during hypoxia, but the molecular underpinnings are largely unknown. Using a lipidomic screen, we found that PLCγ1 is suppressed during hypoxia in KRAS-mutant human lung adenocarcinoma cancer cell lines. Suppression of PLCγ1 in hypoxia promotes a less oxidative cancer cell metabolism state, reduces the formation of mitochondrial reactive oxygen species and switches tumour bioenergetics towards glycolysis by impairing Ca²⁺ entry into the mitochondria. This event prevents lipid peroxidation, antagonizes apoptosis and increases cancer cell proliferation. Accordingly, loss of function of Plcg1 in a mouse model of Kras^G12D-driven lung adenocarcinoma increased the expression of glycolytic genes, boosted tumour growth and reduced survival. In patients with KRAS-mutant lung adenocarcinomas, low PLCγ1 expression correlates with increased expression of hypoxia markers and predicts poor patient survival. Thus, our work reveals a mechanism of cancer cell adaptation to hypoxia with potential therapeutic value.

突变体 KRAS 调节癌细胞的代谢可塑性以在缺氧期间赋予生长优势，但其分子基础在很大程度上是未知的。使用脂质组学筛选，我们发现在 KRAS 突变的人肺腺癌细胞系中，PLCγ1 在缺氧期间受到抑制。在缺氧条件下抑制 PLCγ1 可促进氧化性较低的癌细胞代谢状态，减少线粒体活性氧物质的形成，并通过阻碍 Ca ²⁺进入线粒体将肿瘤生物能量转换为糖酵解。该事件可防止脂质过氧化，拮抗细胞凋亡并增加癌细胞增殖。因此，在Kras ^G12D小鼠模型中Plcg1的功能丧失驱动的肺腺癌增加了糖酵解基因的表达，促进了肿瘤的生长并降低了存活率。在 KRAS 突变肺腺癌患者中，低 PLCγ1 表达与缺氧标志物表达增加相关，并预测患者存活率低。因此，我们的工作揭示了癌细胞适应缺氧的机制，具有潜在的治疗价值。