癌症的起源尚不清楚，因为癌前细胞很少在其原生环境中被追踪。虽然代谢功能的空间区隔对正常的肝功能至关重要，但尚不清楚癌症是否发生在某些区域而不是其他区域，以及是否存在癌症风险的代谢决定因素。Ctnnb1和Arid2突变是肝细胞癌（HCC）中常见的共突变基因，其区域特异性嵌合引入表明，位置和代谢环境决定了克隆命运。Ctnnb1/ arid2驱动的癌症更有可能出现在3区。3区基因Gstm2和Gstm3是HCC有效起始所必需的，部分是通过抑制铁死亡。在肝脏中，HCC发展的区域决定因素可以揭示癌症的代谢脆弱性。
附：英文原文
Title: The origin of hepatocellular carcinoma depends on metabolic zonation
Author: Jason Guo, Roger Liang, Andrew Chung, Zhijie Li, Boyuan Li, Eric Chen, Lin Li, Jingjing Wang, Meng-Hsiung Hsieh, Ivy Xiangyi Fang, Benjamin Kroger, Yunguan Wang, Min Zhu, Xiongzhao Ren, Greg Mannino, Yuemeng Jia, Yonglong Wei, Stephen Moore, Daniel J. Siegwart, Stephen S. Chung, Zixi Wang, Tripti Sharma, Suman Komjeti, Yi Han, Purva Gopal, Guanghua Xiao, Tao Wang, Hao Zhu
Issue&Volume: 2025-11-06
Abstract: The origin of cancer is poorly understood because premalignant cells are rarely followed in their native environments. While the spatial compartmentalization of metabolic functions is critical for proper liver function, it is unknown if cancers arise from some zones but not others, and if there are metabolic determinants of cancer risk. Zone-specific, mosaic introduction of Ctnnb1 and Arid2 mutations, commonly co-mutated genes in hepatocellular carcinoma (HCC), 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.
DOI: adv7129
Source: https://www.science.org/doi/10.1126/science.adv7129