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Journal Articles Journal of Hepatology Year : 2022

Deleting the β-catenin degradation domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumor growth

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Abstract

Background and aims: One-third of hepatocellular carcinomas (HCCs) harbor mutations activating the β-catenin pathway predominantly via mutations in CTNNB1 gene itself. Mouse models of Apc loss-of-function are widely used to mimic β-catenin-dependent tumorigenesis. Given the low prevalence of APC mutations in human HCCs we aimed to generate liver tumors through CTNNB1 exon 3 deletion (βcatΔex3). We then compared βcatΔex3 liver tumors with liver tumors generated via frameshift in exon 15 of Apc (Apcfs-ex15). Methods: We used hepatocyte-specific and inducible mouse models generated through either a Cre-Lox or a CRISPR/Cas9 approach using AAV vectors. Tumors generated by the Cre-Lox models were phenotypically analyzed using immunohistochemistry and were selected for transcriptomic analysis by RNA-sequencing. Mouse RNAseq data were compared to human RNAseq data (8 normal tissues, 48 HCCs, 9 hepatoblastomas) in an integrative analysis. Tumors generated via CRISPR were analyzed using DNA sequencing and immunohistochemistry. Results: Mice with CTNNB1 exon 3 deletion in hepatocytes developed liver tumors indistinguishable from Apcfs-ex15 liver tumors. Both Apcfs-ex15 and βcatΔex3 mouse models induced growth of two phenotypically distinct tumors (differentiated or undifferentiated). Integrative analysis of human and mouse tumors showed that differentiated mouse tumors cluster with well-differentiated human CTNNB1-mutated tumors. Conversely, undifferentiated mouse tumors cluster with human mesenchymal hepatoblastomas and harbor activated YAP signaling. Conclusion: Apcfs-ex15 and βcatΔex3 mouse models both induce growth of tumors that are transcriptionally similar to either well-differentiated and β-catenin-activated human HCCs or mesenchymal hepatoblastomas. Lay summary: New and easy-to-use transgenic mouse models of liver primary cancers have been generated, with mutations in the gene coding beta-catenin, frequent in both adult and pediatric liver primary cancers. The mice develop both types of cancer, constituting a strong preclinical model.
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Dates and versions

inserm-03601766 , version 1 (08-03-2022)

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Robin Loesch, Stefano Caruso, Valérie Paradis, Cecile Godard, Angélique Gougelet, et al.. Deleting the β-catenin degradation domain in mouse hepatocytes drives hepatocellular carcinoma or hepatoblastoma-like tumor growth. Journal of Hepatology, 2022, pp.S0168-8278(22)00130-1. ⟨10.1016/j.jhep.2022.02.023⟩. ⟨inserm-03601766⟩
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