The origin of hepatocellular carcinoma depends on metabolic zonation

• 成果类型: Article
• 署名作者: Guo, Jason; Liang, Roger; Chung, Andrew; Li, Zhijie; Li, Boyuan; Chen, Eric; Li, Lin; Wang, Jingjing; Hsieh, Meng-Hsiung; Fang, Ivy Xiangyi; Kroger, Benjamin; Wang, Yunguan; Zhu, Min; Ren, Xiongzhao; Mannino, Greg; Jia, Yuemeng; Wei, Yonglong; Moore, Stephen; Siegwart, Daniel J.; Chung, Stephen S.; Wang, Zixi; Sharma, Tripti; Komjeti, Suman; Han, Yi; Gopal, Purva; Xiao, Guanghua; Wang, Tao; Zhu, Hao
• 署名单位: University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University System of Ohio; Cincinnati Children's Hospital Medical Center; University of Cincinnati; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center; University of Texas System; University of Texas Southwestern Medical Center
• 刊物名称: SCIENCE
• ISSN/ISSBN: 0036-8075; 1095-9203
• DOI: 10.1126/science.adv7129
• 发表日期: 2026-01-29
• 页码: eadv7129
• 关键词: GLUTATHIONE-S-TRANSFERASE; BETA-CATENIN-MUTATIONS; GLUTAMINE-SYNTHETASE; positive selection; somatic mutations; LIVER HOMEOSTASIS; oxidative stress; genome-wide; expression; cells

摘要

The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. Although the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown whether cancers arise from some zones but not others and whether there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 (catenin beta 1) and Arid2 (AT-rich interaction domain 2) mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), in mouse models showed that position and metabolic context determine clone fates. Ctnnb1/Arid2-driven cancers were much more likely to arise in zone 3. The zone 3 genes Gstm2 and Gstm3 were required for efficient HCC initiation, in part through inhibition of ferroptosis. In the liver, the zonal determinants of HCC development can reveal metabolic vulnerabilities of cancer.