{"doi":"10.1073/pnas.2217826120","title":"PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress","abstract":"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.","journal":"Proceedings of the National Academy of Sciences","year":2023,"id":321915,"datarank":0.5641800173540344,"base_score":3.7612001156935624,"endowment":3.7612001156935624,"self_citation_contribution":0.5641800173540344,"citation_network_contribution":0.0,"self_endowment_contribution":0.5641800173540344,"citer_contribution":0.0,"corpus_percentile":null,"corpus_rank":null,"citation_count":42,"citer_count":0,"citers_with_citation_signal":0,"citers_with_endowment":0,"datacite_reuse_total":0,"is_dataset":false,"is_dataset_confidence":0.9502,"is_data_producer":false,"deposit_databanks":null,"is_oa":true,"file_count":0,"downloads":0,"has_version_chain":false,"published_date":"2023-01-01","fair_score":null,"fair_percentile":null,"algorithm_id":"datarank_citation_only_1hop_v6","ranking_scope":"data_only","authors":[{"id":1034768,"name":"Hyeonhui Kim","orcid":"0000-0002-2036-4851","position":1,"is_corresponding":false},{"id":232495,"name":"Tae Gyu Oh","orcid":"0000-0002-2756-3546","position":2,"is_corresponding":false},{"id":1035297,"name":"Se Kyu Oh","orcid":null,"position":3,"is_corresponding":false},{"id":1035298,"name":"Sugyeong Jo","orcid":null,"position":4,"is_corresponding":false},{"id":1034769,"name":"Minki Kim","orcid":"0000-0002-5587-9935","position":5,"is_corresponding":false},{"id":1035299,"name":"Kyu-Hye Chun","orcid":null,"position":6,"is_corresponding":false},{"id":1034770,"name":"Nahee Hwang","orcid":"0009-0008-3895-3225","position":7,"is_corresponding":false},{"id":1034771,"name":"Suji Lee","orcid":"0000-0002-8770-622X","position":8,"is_corresponding":false},{"id":1034772,"name":"S M Jin","orcid":"0009-0005-3102-7913","position":9,"is_corresponding":false},{"id":232502,"name":"Annette R. Atkins","orcid":"0000-0003-3583-4091","position":10,"is_corresponding":false},{"id":232501,"name":"Ruth T. Yu","orcid":"0000-0002-9527-9627","position":11,"is_corresponding":false},{"id":80487,"name":"Michael Downes","orcid":"0000-0002-6351-9585","position":12,"is_corresponding":false},{"id":317470,"name":"Jae Woo Kim","orcid":"0000-0001-5456-9495","position":13,"is_corresponding":false},{"id":1034773,"name":"Hyun‐Kyung Kim","orcid":"0000-0002-7897-5065","position":14,"is_corresponding":false},{"id":80488,"name":"Ronald M. Evans","orcid":"0000-0002-9986-5965","position":15,"is_corresponding":false},{"id":31969,"name":"Jae-Ho Cheong","orcid":"0000-0002-1703-1781","position":16,"is_corresponding":false},{"id":1034774,"name":"Sungsoon Fang","orcid":"0000-0003-0201-5567","position":17,"is_corresponding":false},{"id":1034767,"name":"Bo Kyung Yoon","orcid":"0000-0003-3436-4665","position":0,"is_corresponding":true}],"reference_count":51,"raw_metadata":{"citation_network_status":"fetched"},"created_at":"2026-07-19T01:07:37.596550Z","pmid":"37192160","pmcid":null,"fwci":null,"citation_percentile":null,"influential_citations":0,"oa_status":null,"license":null,"views":0,"total_file_size_bytes":0,"version_count":0,"fair_f":null,"fair_a":null,"fair_i":null,"fair_r":null,"fair_zscore":null,"fair_rationale":null,"fair_model":null,"fair_agent_version":null,"fair_fulltext_source":null,"fair_has_llm":null,"fair_computed_at":null,"clinical_trials":[],"software_tools":[],"db_accessions":[],"linked_datasets":[],"topics":[]}