Hot Zones for Liver Cancer: Metabolic Zonation, Ferroptosis, and the Origins of HCC

异位表达 生物 肝细胞癌 癌症研究 基因 突变体 突变 氧化应激 肝癌 癌症 遗传学 程序性细胞死亡 致癌物 谷胱甘肽 肝细胞 细胞生物学 癌变 基因表达 机制(生物学) 表型 癌细胞 遗传异质性
作者
Katherine M. Barrows,Natalie Porat‐Shliom
出处
期刊:Cancer Research [American Association for Cancer Research]
卷期号:86 (6): 1347-1350 被引量:1
标识
DOI:10.1158/0008-5472.can-25-5839
摘要

Hepatocellular carcinoma (HCC) is a major cause of cancer-related death and is often resistant to treatment, partly because it develops after decades of chronic injury in a metabolically heterogeneous organ. Anatomically, the liver is organized into lobules with three concentric zones, each with distinct gene expression and metabolic programs; however, it remains unclear whether cancer favors any particular zone. In a new study, Guo and colleagues use sophisticated mouse genetics to introduce cancer-driving mutations in specific liver zones. By combining this approach with spatial transcriptomics, they track premalignant hepatocytes within the tissue microenvironment. They discover that periportal zone 1 clones expand and persist more than the rare, relatively less fit clones in pericentral zone 3. Paradoxically, however, HCC mainly arises from zone 3 hepatocytes across multiple oncogenic models, revealing a striking disconnect between clonal expansion and tumorigenic potential. A functional screen of transcripts enriched in zone 3 identifies the glutathione S-transferases Gstm2 and Gstm3 as key factors in transformation. These enzymes maintain redox balance and suppress ferroptosis in early mutant cells. Genetic deletion, hepatocyte-specific knockdown, and irreversible chemical inhibition of GSTMs all increase oxidative stress and ferroptosis, preventing tumor formation. Ectopic expression of Gstm3 in zone 1 is sufficient to reprogram these cells into a cell-of-origin compartment. These findings define the "tumorigenic zonation" of the liver and suggest that targeting ferroptosis vulnerability could be a promising therapeutic strategy for HCC.
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