PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress

Molecular classification of gastric cancer (GC) identified a subgroup of patients showing chemoresistance and poor prognosis, termed SEM (Stem-like/Epithelial-to-mesenchymal transition/Mesenchymal) type in this study. Here, we show that SEM-type GC exhibits a distinct metabolic profile characterized by high glutaminase (GLS) levels. Unexpectedly, SEM-type GC cells are resistant to glutaminolysis inhibition. We show that under glutamine starvation, SEM-type GC cells up-regulate the 3 phosphoglycerate dehydrogenase (PHGDH)-mediated mitochondrial folate cycle pathway to produce NADPH as a reactive oxygen species scavenger for survival. This metabolic plasticity is associated with globally open chromatin structure in SEM-type GC cells, with ATF4/CEBPB identified as transcriptional drivers of the PHGDH-driven salvage pathway. Single-nucleus transcriptome analysis of patient-derived SEM-type GC organoids revealed intratumoral heterogeneity, with stemness-high subpopulations displaying high GLS expression, a resistance to GLS inhibition, and ATF4/CEBPB activation. Notably, coinhibition of GLS and PHGDH successfully eliminated stemness-high cancer cells. Together, these results provide insight into the metabolic plasticity of aggressive GC cells and suggest a treatment strategy for chemoresistant GC patients.

Automated summary

Molecular classification of gastric cancer identified a subgroup of patients with poor prognosis and chemoresistance, called SEM type, which exhibits a distinct metabolic profile characterized by high levels of glutaminase. These SEM type gastric cancer cells are resistant to glutaminolysis inhibition due to the upregulation of the PHGDH-mediated mitochondrial folate cycle pathway under glutamine starvation. The metabolic plasticity in SEM type GC cells is associated with open chromatin structure and driven by ATF4/CEBPB. The coinhibition of GLS and PHGDH effectively eliminates stemness-high cancer cells, providing a potential treatment strategy for chemoresistant GC patients.