Faculty, Staff and Student Publications

Publication Date

1-29-2026

Journal

Science

DOI

10.1126/science.adv7129

PMID

41196951

PMCID

PMC12999168

PubMedCentral® Posted Date

3-19-2026

PubMedCentral® Full Text Version

Author MSS

Abstract

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.

Keywords

Animals, Humans, Mice, beta Catenin, Carcinoma, Hepatocellular, Ferroptosis, Glutathione Transferase, Liver, Liver Neoplasms, Mutation, Transcription Factors

Published Open-Access

yes

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