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

Bo Kyung Yoon, Hyeonhui Kim, Tae Gyu Oh, Se Kyu Oh, Sugyeong Jo, Minki Kim, Kyu Hye Chun, Nahee Hwang, Suji Lee, Suyon Jin, Annette R. Atkins, Ruth T. Yu, Michael Downes, Jae Woo Kim, Hyunkyung Kim, Ronald M. Evans, Jae Ho Cheong, Sungsoon Fang

Research output: Contribution to journalArticlepeer-review

7 Citations (Scopus)

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.

Original languageEnglish
Article numbere2217826120
JournalProceedings of the National Academy of Sciences of the United States of America
Volume120
Issue number21
DOIs
Publication statusPublished - 2023 May 23

Bibliographical note

Publisher Copyright:
Copyright © 2023 the Author(s). Published by PNAS. This article is distributed under Creative Commons Attribution-NonCommercial-NoDerivatives License 4.0 (CC BY-NC-ND).

ASJC Scopus subject areas

  • General

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