ZFIN ID: ZDB-PUB-191003-2
Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish
Kalasekar, S.M., Kotiyal, S., Conley, C., Phan, C., Young, A., Evason, K.J.
Date: 2019
Source: Biology Open   8(10): (Journal)
Registered Authors:
Keywords: Beta-catenin, CreLox, Hepatocellular carcinoma, Single-cell RNAseq, Zebrafish
Microarrays: GEO:GSE137784, GEO:GSE137787, GEO:GSE137788
MeSH Terms: none
PubMed: 31575545 Full text @ Biol. Open
Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in 1) a small number of hepatocytes in early development; or 2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca, and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.