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. 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.

成纤维细胞生长因子19（Fibroblast growth factor 19, FGF19）基因扩增是人类肝细胞癌（hepatocellular carcinoma, HCC）中常见的分子事件。其编码的蛋白作为一种激素，具备多项对肝脏有益的代谢调控功能，这推动了其结构类似物的研发，用于治疗非酒精性脂肪性肝炎（Nonalcoholic Steatohepatitis, NASH）等代谢紊乱类疾病。目前研究最为深入的类似物为阿达芬明（Aldafermin, NGM282），既往研究证实其单独给药时无致瘤性。然而，FGF19类似物与肝细胞癌中常见的失调通路之间潜在的致瘤协同作用尚未被系统探究。
本研究采用水动力基因转染与重组蛋白注射的实验策略，探究FGF19及其啮齿类同源基因FGF15、FGF19类似物阿达芬明与肝细胞癌常见致病事件之间的致瘤协同效应。研究发现，FGF15/19或阿达芬明与肝细胞过表达的Myc之间存在显著的协同致瘤作用。由此诱导形成的肿瘤可在短周期（2~4周）内出现，肿瘤分化程度良好，且表达典型的肝细胞癌标志物：甲胎蛋白（alpha foetoprotein）与磷脂酰肌醇蛋白聚糖3（Glypican 3）。转录组学与病理学分析结果显示，Myc/FGF19与Myc/阿达芬明诱导的肿瘤分子特征几乎完全一致。鉴于目前针对肝硬化患者的临床研究正在开展（肝硬化是肝细胞癌高发的易感状态），本研究结果具有潜在的临床转化价值。
本研究通过水动力基因转染技术，在C57BL/6小鼠（每组n=5）的部分肝细胞亚群中分别表达FGF19、阿达芬明与MYC。收集肿瘤组织与健康肝组织后，送检进行批量RNA测序（Bulk RNA-seq）。