LAUSR

To sustain rapid tumor growth, glioma cells must have the ability to adapt in order to survive in their rapidly changing and often harsh microenvironment. A recent study in the journal Nature elegantly describes a novel survival mechanism and sensitivity to glycine levels in glioblastoma cells as a result of metabolic rewiring in ischemic conditions. The authors initially found that the enzyme glycine decarboxylase (GLDC), whose loss is associated with severe neurodevelopmental defects, is highly expressed in glioblastoma. GLDC is part of an enzyme complex that catalyzes the degradation of glycine. GLDC knockdown in glioblastoma cells led to glycine accumulation and toxicity, as did addition of a cell-permeable glycine analog to the culture medium. The authors found that glycine toxicity in the absence of GLDC resulted from accumulation of toxic metabolites, including aminoacetone and methylgloxal. They then examined the upstream enzyme serine hydroxymethyltransferase 2 (SHMT2), which acts as a key source of glycine in proliferating cells by converting serine to glycine. Accordingly, SHMT2 suppression prevented glycine accumulation and toxicity in GLDC-knockdown glioblastoma cells. In patient tumor specimens, SHMT2 and GLDC were highly expressed in pseudopallisading cells, suggesting a potential role in ischemia. Consistent with this observation, knockdown of SHMT2 slowed glioblastoma cell growth under low-oxygen conditions, and cell survival was impaired in vivo, which was rescued by SHMT2 overexpression. Further metabolic analysis revealed that suppression of SHMT2 increased pyruvate kinase M2 (PKM2) flux and oxygen consumption. Thus, metabolic rewiring in ischemic glioma cells involves increased SHMT2 levels, which lowers oxygen consumption via PKM2. Upregulation of SHMT2 also creates a dependence on glycine clearance by GLDC. This is a novel therapeutic vulnerability in ischemic glioma cells, and GLDC could therefore be a potential metabolic target for future development.