Department of Stem Cell Biology, Research Institute for Radiation Biology and Medicine, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima, 734-8553, Japan.
Pharmaceuticals and Life Sciences Division, Shimadzu Techno-Research, Inc., 1, Nishinokyo-shimoai-cho, Nakagyou-ku, Kyoto, 604-8436, Japan.
Nat Commun. 2020 Sep 17;11(1):4681. doi: 10.1038/s41467-020-18491-9.
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可以方便地定量分析细胞内的脂质成分，但对于癌细胞中脂质代谢的调节知之甚少。在这里，我们表明，编码溶血磷脂酶 D 酶的 Gdpd3 基因的破坏显著降低了体内小鼠慢性髓系白血病 (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。Gdpd3 的缺失还激活了 AKT/mTORC1 信号通路和细胞周期进程，同时抑制了 CML 干细胞核内 Foxo3a/β-catenin 相互作用。引人注目的是，携带编码富含亮氨酸重复 (LRR) 的 G 蛋白偶联受体 (GPCR) 的 Lgr4/Gpr48 基因的功能获得性突变的 CML 干细胞，在体内表现出不足的起始疾病能力。我们的数据表明，溶血磷脂代谢是体内 CML 干细胞维持所必需的，这为癌症复发建立了一个新的、具有生物学意义的机制，该机制独立于癌基因成瘾。
