FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis

Fibroblast growth factor 19 (FGF19) gene amplification is a common event in human hepatocellular carcinoma (HCC). The protein it encodes acts as a hormone with multiple metabolic functions beneficial for the liver, which has led to the development of analogues for the treatment of metabolic disorders such as Nonalcoholic Steatohepatitis (NASH). The most studied analogue is Aldafermin (NGM282), with previous reports showing the absence of oncogenic properties when given alone. However, potential oncogenic cooperation with frequent disrupted pathways in HCC have not been studied. Here, we used hydrodynamic gene transfer and recombinant protein injection to study oncogenic cooperation between FGF19 and its rodent orthologue FGF15, FGF19 analogue Aldafermin and common HCC events. We found a strong cooperation between FGF15/19 or Aldafermin and hepatocyte overexpression of Myc. The resulting tumours appeared in a short frame (2 to 4 weeks), were well differentiated, and expressed typical HCC markers (alpha foetoprotein and glypican 3). Transcriptomic and pathological analyses showed that Myc/FGF19 and Myc/Aldafermin tumours were almost identical. Our findings could be clinically relevant since clinical studies are currently ongoing in patients with cirrhosis, a condition associated with high susceptibility to HCC development. Overall design: Hydrodynamic gene transfer was made a C57Bl6 mice (n=5/conditions) to express FGF19, Aldafermin and MYC in a subtype of hepatocytes. Tumoral or healthy liver was collected and sent for Bulk RNAseq.