ena-STUDY-NATIONAL CANCER CENTER-13-06-2019-06:57:04:019-230
ARS2/MAGL signaling in glioblastoma stem cells promotes self-renewal and M2-like polarization of tumor-associated macrophage
The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailedmolecular mechanisms underlying the relationship between these two cell types remainunclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger proteinthat is essential for early mammalian development, plays critical roles in GSC maintenanceand M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL,encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicityof GSCs through production of prostaglandin E2 (PGE2), which stimulates ß-cateninactivation and M2-like TAM polarization. Specific knockdown of ARS2 or MAGLsignificantly suppressed self-renewal and tumor growth, and increased survival in a mouseintracranial xenograft model of GSCs. We identified M2-like signature downregulated bywhich MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mousexenograft model. The M2-like signature was enriched in mesenchymal subtype and predictedpoor survival in GBM patients. Taken together, our results suggest that blocking the interplaybetween GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially noveltherapeutic option for GBM patients.
The interplay between glioblastoma stem cells (GSCs) and tumor-associated macrophages (TAMs) promotes progression of glioblastoma multiforme (GBM). However, the detailedmolecular mechanisms underlying the relationship between these two cell types remainunclear. Here, we demonstrate that ARS2 (arsenite-resistance protein 2), a zinc finger proteinthat is essential for early mammalian development, plays critical roles in GSC maintenanceand M2-like TAM polarization. ARS2 directly activates its novel transcriptional target MGLL,encoding monoacylglycerol lipase (MAGL), to regulate the self-renewal and tumorigenicityof GSCs through production of prostaglandin E2 (PGE2), which stimulates ß-cateninactivation and M2-like TAM polarization. Specific knockdown of ARS2 or MAGLsignificantly suppressed self-renewal and tumor growth, and increased survival in a mouseintracranial xenograft model of GSCs. We identified M2-like signature downregulated bywhich MAGL-specific inhibitor, JZL184, increased survival rate significantly in the mousexenograft model. The M2-like signature was enriched in mesenchymal subtype and predictedpoor survival in GBM patients. Taken together, our results suggest that blocking the interplaybetween GSCs and TAMs by targeting ARS2/MAGL signaling offers a potentially noveltherapeutic option for GBM patients.