Increased expression of the Fibroblast Growth Factor (FGF19), a hormone whose physiological function is the regulation of bile acid and glucose homeostasis, is a hallmark of a sub-group of aggressive hepatocellular carcinoma (HCC). Analogs have been developed aiming to mimic the hepatoprotective metabolic effects of FGF19, while being theoretically devoid of its oncogenic effects. FGF19 analogs, as well as inhibitors of its signaling, are under investigation for treatment of metabolic disorders and HCC, respectively.
In this study, supervised by Damien Grégoire, the authors investigated oncogenic cooperation between FGF19, or its analogs, and pathways frequently mutated in HCC.
Using a preclinical mouse model, Ursic-Bedoya, Desandré et al. report that while FGF19 is by itself a weak oncogene, it efficiently cooperates with several oncogenic events characteristic of HCC, such as activation of the Wnt/b-catenin pathway or increased Myc expression. Strikingly, similar results were obtained with FGF19 analog Aldafermin (NGM282), notwithstanding the reported lack of oncogenic activity of this analog. In particular, even a short treatment with systemic administration of recombinant proteins sparked the formation of proliferative foci of MYC-transfected hepatocytes.
These findings indicate that FGF19/FGFR4 pathway activation cooperates with Myc to promote aggressive HCC. Moreover, Ursic-Bedoya, Desandré and colleagues show that Aldafermin retains oncogenic properties in this context. Since Myc pathway is often deregulated in patients with MASH or cirrhosis, this report urges caution in the clinical application of FGF19-analogs, particularly in the context of liver diseases and their associated genetic alterations.
https://www.embopress.org/doi/epdf/10.1038/s44321-023-00021-x
Ursic-Bedoya J.*, Desandré G.*, Chavey C., Marie P., Polizzi A., Rivière B., Guillou H., Assenat E., Hibner U., Grégoire D. (2024)
FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis.
EMBO mol med, 2024
https://doi.org/10.1038/s44321-023-00021-x
