Abstract 1100: Fascin-1 inhibitor decreases hepatoblastoma cells tumorigenicity via YAP 1
Authors: DIF Lydia , Martin Amandine , Basbous Sara , Manaud Gregoire , Moreau Violaine 
Published: March 2024

Introduction: Hepatoblastoma (HB) is a liver tumor that arises in children. It's a sporadic malignancy that is often overly aggressive. The current treatment consists of chemotherapy. However, chemotherapy in young patients has disastrous and long-term side effects such as ototoxicity, cardiomyopathy, and infertility. Thus, alternative strategies are needed. One hint is to target the most common mutations in HB. It has been demonstrated that 90% of HB tumors are mutated for the Wnt pathway effector ß-catenin. This mutation leads to an aberrant constitutive activation of Wnt/ß-catenin signaling. Here, we investigate one of ß-catenin transcriptional targets, Fascin-1 that is found up-regulated in many tumors. Fascin1 affects actin organization into bundles, and this leads to cell migration and invasion. Whereas Fascin-1 is absent from normal hepatocytes, we found its expression associated to the poor prognosis C2 subtype of HB. In both human and murine HB samples, Fascin-1 is associated to undifferentiated tumor cells. We further demonstrated that Fascin-1 expression modulates tumor hepatocyte differentiation status through gene expression. In this study, we investigate how Fascin-1 can regulate tumor cell plasticity and whether Fascin-1 is a druggable target in HB tumors.

Methods: We use two classical HB model cells Huh6 and HepG2 and 3 Patient-Derived-Xenograft cell lines. We explore the effect of Fascin-1 actin-bundling activity impairment by using inhibitors, on invasion and migration using Trans-well and wound-healing assays. We follow proliferation and cell death by Flow cytometry and investigate gene expression by PCR and reporter assay. We investigate Fascin modulation of the kinome with PamGene technology.

Results: We show that the inhibition of Fascin actin-binding activity decreases cell invasion and migration as well as proliferation. We show an increase of cell death in Huh6/HepG2 cells but not in the PDX models. A cell cycle arrest is induced, and the cells become senescent. Differentiation genes are overexpressed and EMT genes are repressed. Yap expression is downregulated; Yap promoter activity is downregulated, and Yap is found translocated into the cytoplasm upon Fascin-1 inhibition. These data suggest that Fascin inhibition decreases tumors cell invasion, induces cell senescence, and favors a switch towards a differentiated and these effects on the cells are mediated via the Hippo pathway. The kinome is also modulated.

Conclusion: Fascin-1 is an interesting target in hepatoblastoma, commercialized phase-2 drugs are available, and this study will confirm the potential use of those drugs in HB treatment and elucidate by which mechanism Fascin-1 inhibition impacts tumors.

Citation Format: Lydia DIF, Amandine Martin, Sara Basbous, Gregoire Manaud, Violaine Moreau. Fascin-1 inhibitor decreases hepatoblastoma cells tumorigenicity via YAP 1 [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2024; Part 1 (Regular Abstracts); 2024 Apr 5-10; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2024;84(6_Suppl):Abstract nr 1100.