Abstract:
Ewing sarcoma is a cancer of bone and soft tissue in children and young adults primarily driven by the EWS-FLI1 fusion oncoprotein, which has been undruggable. Here, we report that Ewing sarcoma depends on secreted sphingomyelin phosphodiesterase 1 (SMPD1), a ceramide-generating enzyme, and ceramide. We find that G-protein-coupled receptor 64 (GPR64)/adhesion G-protein-coupled receptor G2 (ADGRG2) responds to ceramide and mediates critical growth signaling in Ewing sarcoma. We show that ceramide induces the cleavage of the C-terminal intracellular domain of GPR64, which translocates to the nucleus and restrains the protein levels of RIF1 in a manner dependent on SPOP, a substrate adaptor of the Cullin3-RING E3 ubiquitin ligase. We demonstrate that both SMPD1 and GPR64 are transcriptional targets of EWS-FLI1, indicating that SMPD1 and GPR64 are EWS-FLI1-induced cytokine-receptor dependencies. These results reveal the SMPD1-ceramide-GPR64 pathway, which drives Ewing sarcoma growth and is amenable to therapeutic intervention.
摘要:
尤文肉瘤是一种主要由EWS-FLI1融合癌蛋白驱动的儿童和年轻人的骨和软组织癌,这是不可麻醉的。这里,我们报道尤文肉瘤依赖于分泌的鞘磷脂磷酸二酯酶1(SMPD1),一种神经酰胺生成酶,还有神经酰胺.我们发现G蛋白偶联受体64(GPR64)/粘附G蛋白偶联受体G2(ADGRG2)响应神经酰胺并介导尤因肉瘤的关键生长信号。我们显示神经酰胺诱导GPR64的C末端细胞内结构域的裂解,其易位到细胞核并以依赖于SPOP的方式抑制RIF1的蛋白质水平,Cullin3-RINGE3泛素连接酶的底物衔接子。我们证明SMPD1和GPR64都是EWS-FLI1的转录靶标,表明SMPD1和GPR64是EWS-FLI1诱导的细胞因子受体依赖性。这些结果揭示了SMPD1-神经酰胺-GPR64途径,推动尤文肉瘤生长,适合治疗干预。