A new model for the study of liver cancer


In an article recently published in the Journal of Hepatology, Sabine Colnot’s team describes the creation of a new mouse model of primary liver cancer using the CrispR-Cas9 technique (Nobel Prize 2020).

Primary liver cancer is the 3rd most deadly cancer in the world. Its most frequent form is hepatocellular carcinoma (HCC), associated in humans with viral hepatitis, liver cirrhosis, or fatty liver developed in the context of metabolic syndrome (in particular obesity). One third of HCCs are associated with mutations activating the ß-catenin signaling pathway, mutations occurring mainly in the β-catenin gene itself, the CTNNB1 gene. However, most experimental liver cancer models in mice have been created via mutation of the APC gene, a partner in this β-catenin signaling.

Using the CrispR-Cas9 system, transgenic mice with a mutated β-catenin gene can be created. These mice develop two types of primary liver cancer (hepatocellular carcinomas and hepatoblastomas) whose characteristics are very similar to this type of cancer in humans.

Sabine Colnot and her team therefore wished to create a mouse model closer to the genetic reality of these tumors, i.e. carrying mutations in CTNNB1, the β-catenin gene. 

Robin Loesch, a PhD student in the team, used the CRISPR/Cas9 molecular scissors technique in vivo in mice to delete part of the CTNNB1 gene (the most frequent genetic mutation in this cancer in France), resulting in activation of the β-catenin signaling pathway. This revolutionary molecular scissors technique allows genetic modification of mouse liver cells by simple intravenous injection of viral particles that express the CrispR-Cas9 system modified to induce expression of the mutant β-catenin. These CRISPR-β-catenin mice develop hepatocellular carcinomas (HCC), but also tumors similar to hepatoblastomas (HB), the childhood liver cancer.

The researchers showed that tumors generated in mice by the β-catenin gene mutation or by the APC gene mutation are identical. They also showed that the gene expression of tumors from CRISPR-β-catenin mice, and that of tumors taken from humans, in a cohort of patients with HCC or HB, are very similar, which supports the interest of this new mouse model. This study was conducted in collaboration with Jessica Zucman-Rossi’s team at the Centre de Recherche des Cordeliers.

This new model is therefore valuable for studying these two types of primary liver cancers in humans. It also represents a technological advance that could replace the classic Cre-Lox approach, which is much more cumbersome, to generate targeted tumors in mice.

On a more general level, at a time when immunotherapy is emerging as a therapeutic approach for patients with hepatocellular carcinoma, it should be noted that HCCs with β-catenin mutations are mostly described as “cold” tumors, which are resistant to immunotherapy. These HCCs therefore require new treatment regimens. CRISPR-β-catenin mice will both provide a better understanding of the mechanisms of resistance to treatments, and allow in vivo testing of therapeutic alternatives in a relevant liver cancer model.

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Contact : Sabine Colnot : sabine.colnot@inserm.fr