Although advanced lipidomics technology facilitates quantitation of intracellular lipid components, little is known about the regulation of lipid metabolism in cancer cells. Here, we show that disruption of the Gdpd3 gene encoding a lysophospholipase D enzyme significantly decreased self-renewal capacity in murine chronic myelogenous leukaemia (CML) stem cells in vivo. Sophisticated lipidomics analyses revealed that Gdpd3 deficiency reduced levels of certain lysophosphatidic acids (LPAs) and lipid mediators in CML cells. Loss of Gdpd3 also activated AKT/mTORC1 signalling and cell cycle progression while suppressing Foxo3a/β-catenin interaction within CML stem cell nuclei. Strikingly, CML stem cells carrying a hypomorphic mutation of Lgr4/Gpr48, which encodes a leucine-rich repeat (LRR)-containing G-protein coupled receptor (GPCR) acting downstream of Gdpd3, displayed inadequate disease-initiating capacity in vivo. Our data showing that lysophospholipid metabolism is required for CML stem cell maintenance in vivo establish a new, biologically significant mechanism of cancer recurrence that is independent of oncogene addiction.

尽管先进的脂质组学技术促进了细胞内脂质成分的定量，但对癌细胞中脂质代谢的调节知之甚少。在这里，我们显示编码溶血磷脂酶 D 酶的Gdpd3基因的破坏显着降低了体内小鼠慢性粒细胞白血病 (CML) 干细胞的自我更新能力。复杂的脂质组学分析表明，Gdpd3缺乏会降低 CML 细胞中某些溶血磷脂酸 (LPA) 和脂质介质的水平。的损失Gdpd3也被激活AKT / mTORC1信号和细胞周期进展，同时抑制内CML Foxo3a的/β连环蛋白相互作用干细胞的细胞核。引人注目的是，携带Lgr4/Gpr48 亚型突变的 CML 干细胞编码在 Gdpd3 下游起作用的富含亮氨酸重复序列 (LRR) 的 G 蛋白偶联受体 (GPCR)，在体内显示出不足的疾病引发能力。我们的数据显示溶血磷脂代谢是体内 CML 干细胞维持所必需的，这建立了一种新的、具有生物学意义的癌症复发机制，该机制独立于癌基因成瘾。