Antagonism between wild-type and mutant β-catenin controls hepatoblastoma differentiation via fascin-1

Caroline Gest (1) , Sandra Sena (1) , Lydia Dif (1) , Véronique Neaud (1) , Robin Loesch (2) , Nathalie Dugot-Senant , Lisa Paysan (1) , Léo Piquet (1) , Terezinha Robbe (1) , Nathalie Allain (1) , Doulaye Dembélé (3) , Catherine Guettier , Paulette Bioulac-Sage (1) , Anne Rullier , Brigitte Le Bail (1) , Christophe F. Grosset (1) , Frédéric Saltel (1) , Valérie Lagrée (1) , Sabine Colnot (2) , Violaine Moreau (1)

1 Inserm U1312 - BRIC - BoRdeaux Institute in onCology
2 CRC (UMR_S_1138 / U1138) - Centre de Recherche des Cordeliers
3 IGBMC - Institut de Génétique et de Biologie Moléculaire et Cellulaire

BACKGROUND & AIMS: β-catenin is a well-known effector of the Wnt pathway, and a key player in cadherin-mediated cell adhesion. Oncogenic mutations of β-catenin are very frequent in paediatric liver primary tumours. Those mutations are mostly heterozygous, which allows the co-expression of wild-type (WT) and mutated β-catenins in tumour cells. We investigated the interplay between WT and mutated β-catenins in liver tumour cells, and searched for new actors of the β-catenin pathway. METHODS: Using an RNAi strategy in β-catenin-mutated hepatoblastoma (HB) cells, we dissociated the structural and transcriptional activities of β-catenin, which are carried mainly by WT and mutated proteins, respectively. Their impact was characterised using transcriptomic and functional analyses. We studied mice that develop liver tumours upon activation of β-catenin in hepatocytes (APCKO and β-cateninΔexon3 mice). We used transcriptomic data from mouse and human HB specimens, and used immunohistochemistry to analyse samples. RESULTS: We highlighted an antagonistic role of WT and mutated β-catenins with regard to hepatocyte differentiation, as attested by alterations in the expression of hepatocyte markers and the formation of bile canaliculi. We characterised fascin-1 as a transcriptional target of mutated β-catenin involved in tumour cell differentiation. Using mouse models, we found that fascin-1 is highly expressed in undifferentiated tumours. Finally, we found that fascin-1 is a specific marker of primitive cells including embryonal and blastemal cells in human HBs. CONCLUSIONS: Fascin-1 expression is linked to a loss of differentiation and polarity of hepatocytes. We present fascin-1 as a previously unrecognised factor in the modulation of hepatocyte differentiation associated with β-catenin pathway alteration in the liver, and as a new potential target in HB. IMPACT AND IMPLICATIONS: The FSCN1 gene, encoding fascin-1, was reported to be a metastasis-related gene in various cancers. Herein, we uncover its expression in poor-prognosis hepatoblastomas, a paediatric liver cancer. We show that fascin-1 expression is driven by the mutated beta-catenin in liver tumour cells. We provide new insights on the impact of fascin-1 expression on tumour cell differentiation. We highlight fascin-1 as a marker of immature cells in mouse and human hepatoblastomas.

Domaines: Génétique

Caroline Gest, Sandra Sena, Lydia Dif, Véronique Neaud, Robin Loesch, et al.. Antagonism between wild-type and mutant β-catenin controls hepatoblastoma differentiation via fascin-1. JHEP Reports Innovation in Hepatology, 2023, 5 (5), pp.100691. ⟨10.1016/j.jhepr.2023.100691⟩. ⟨hal-04458624⟩