The origin of hepatocellular carcinoma depends on metabolic zonation
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 <i>Ctnnb1</i> (catenin beta 1) and <i>Arid2</i> (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. <i>Ctnnb1</i>/<i>Arid2</i>-driven cancers were much more likely to arise in zone 3. The zone 3 genes <i>Gstm2</i> and <i>Gstm3</i> 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.
Authors
- Yuemeng Jia (ORCID: https://orcid.org/0000-0002-8019-1534)
- Suman Komjeti
- Zhijie Li (ORCID: https://orcid.org/0009-0003-9610-0953)
- Daniel J. Siegwart (ORCID: https://orcid.org/0000-0003-3823-1931)
- Guanghua Xiao (ORCID: https://orcid.org/0000-0001-9387-9883)
- Yi Han (ORCID: https://orcid.org/0000-0002-2835-9280)
- Roger J. Liang (ORCID: https://orcid.org/0000-0002-3950-9520)
- Stephen S. Chung (ORCID: https://orcid.org/0000-0002-1433-7419)
- Tripti Sharma (ORCID: https://orcid.org/0000-0003-1799-1157)
- Jason Guo (ORCID: https://orcid.org/0000-0003-0062-5118)
- Hao Zhu (ORCID: https://orcid.org/0000-0002-8417-9698)
- Purva Gopal (ORCID: https://orcid.org/0000-0001-7125-695X)
- Benjamin Kroger (ORCID: https://orcid.org/0000-0001-5675-9102)
- Andrew Chung (ORCID: https://orcid.org/0000-0001-5273-1428)
- Yunguan Wang (ORCID: https://orcid.org/0000-0003-0767-6188)
- Yonglong Wei (ORCID: https://orcid.org/0000-0001-6152-7963)
- Xuejun Ren (ORCID: https://orcid.org/0000-0001-6132-1228)
- Jingjing Wang
- Lin Li (ORCID: https://orcid.org/0000-0001-8715-7980)
- Tao Wang (ORCID: https://orcid.org/0000-0002-4355-149X)
- Zixi Wang (ORCID: https://orcid.org/0000-0002-9354-1206)
- Eric Chen (ORCID: https://orcid.org/0000-0001-9772-2357)
- Boyuan Li (ORCID: https://orcid.org/0000-0001-9549-9884)
- Meng-Hsiung Hsieh (ORCID: https://orcid.org/0000-0001-9791-1318)
- Stephen Moore (ORCID: https://orcid.org/0000-0003-4156-5350)
- Min Zhu (ORCID: https://orcid.org/0000-0002-8417-9698)
- Ivy Xiangyi Fang (ORCID: https://orcid.org/0000-0002-9024-4281)
- Greg Mannino (ORCID: https://orcid.org/0000-0002-4268-2260)
Institutions
- Cincinnati Children's Hospital Medical Center (US)
- Children’s Institute (US)
- The University of Texas Southwestern Medical Center (US)
Publication Details
- Journal
- Science
- Published
- 2025-11-06
- DOI
- https://doi.org/10.1126/science.adv7129
- Citations
- 7
- Primary Topic
- Ferroptosis and cancer prognosis
- Type
- article
- Field-Weighted Citation Impact
- 10.63