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Proc. Natl. Acad. Sci. USA, 2023 May 23;120(21):e2217826120 | https://doi.org/10.1073/pnas.2217826120 PHGDH preserves one-carbon cycle to confer metabolic plasticity in chemoresistant gastric cancer during nutrient stress

Bo Kyung Yoon^a,b,c,1, Hyeonhui Kim^a,1, Tae Gyu Oh^d, Se Kyu Oh^e, Sugyeong Jo^a, Minki Kim^a, Kyu-Hye Chun^a,b,c, Nahee Hwang^a,b,c, Suji Lee^a, Suyon Jin^a, Annette R. Atkins^d, Ruth T. Yu^d, Michael Downes^d, Jae-woo Kim^a,b,c,2, Hyunkyung Kim^f,g,2, Ronald M. Evans^d,2, Jae-Ho Cheong^{a,b,c,h,i,j,2}, and Sungsoon Fang^a,e,k,2

^aGraduate school of Medical Science, Brain Korea 21 Project, Yonsei University College of Medicine, Seoul 03722, Korea;
^bDepartment of Biochemistry and Molecular Biology, Yonsei University College of Medicine, Seoul 03722, Korea;
^cChronic Intractable Disease for Systems Medicine Research Center, Yonsei University College of Medicine, Seoul 03722, Korea;
^dGene Expression Laboratory, Salk Institute for Biological Sciences, La Jolla, CA 92037;
^eKynogen corporation, Suwon 16229, Korea;
^fDepartment of Biochemistry and Molecular Biology, Korea University College of Medicine, Seoul 02841, Korea;
^gDepartment of Biomedical Sciences, BK21 Graduate Program, Korea University College of Medicine, Seoul 02841, Korea;
^hDepartment of Surgery, Yonsei University College of Medicine, Seoul 03722, Korea;
ⁱDepartment of Biomedical Systems Informatics, Yonsei University College of Medicine, Seoul 03722, Korea;
^jVeraverse Inc., Seoul 06162, Korea; and kSeverance Biomedical Science Institute, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul 06230, Korea

¹B.K.Y. and H.K. contributed equally to this work.
²To whom correspondence may be addressed. : Jae-woo Kim, Hyunkyung Kim, Ronald M. Evans, Jae-Ho Cheong, Sungsoon Fang

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.

논문정보

형식Research article
게재일2023년 05월 (BRIC 등록일 2023-05-19)
연구진국내(교신)+국외 연구진
분야 생명과학 > 세포생물학

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