FGF19 and its analog Aldafermin cooperate with MYC to induce aggressive hepatocarcinogenesis
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ABSTRACT:
PROVIDER: PRJNA1015606 | ENA |
REPOSITORIES: ENA
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Project description: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.
2023-12-18 | GSE242953 | GEO
Project description:FGF19 hormone has pleiotropic metabolic functions, including the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities. Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormone's metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes. The fact that FGF19 analog Aldafermin is not fully devoid of the hormone's oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver.
| S-SCDT-10_1038-S44321-023-00021-X | biostudies-other
Project description:FGF19 hormone has pleiotropic metabolic functions, including the modulation of insulin sensitivity, glucose/lipid metabolism and energy homeostasis. On top of its physiological metabolic role, FGF19 has been identified as a potentially targetable oncogenic driver, notably in hepatocellular carcinoma (HCC). Nevertheless, FGF19 remained an attractive candidate for treatment of metabolic disease, prompting the development of analogs uncoupling its metabolic and tumor-promoting activities. Using pre-clinical mice models of somatic mutation driven HCC, we assessed the oncogenicity of FGF19 in combination with frequent HCC tumorigenic alterations: p53 inactivation, CTNNB1 mutation, CCND1 or MYC overexpression. Our data revealed a strong oncogenic cooperation between FGF19 and MYC. Most importantly, we show that this oncogenic synergy is conserved with a FGF19-analog Aldafermin (NGM282), designed to solely mimic the hormone's metabolic functions. In particular, even a short systemic treatment with recombinant proteins triggered rapid appearance of proliferative foci of MYC-expressing hepatocytes. The fact that FGF19 analog Aldafermin is not fully devoid of the hormone's oncogenic properties raises concerns in the context of its potential use for patients with damaged, mutation-prone liver.
| S-EPMC10897482 | biostudies-literature
Project description:Double transgenic mice with hepatocyte-specific expression of AEG-1 and c-Myc show aggressive HCC compared to single transgenics. Gene expression was analyzed to understand the molecular mechanism by which AEG-1 and c-Myc cooperate to promote hepatocarcinogenesis. Livers were collected from naïve adult mice (3 mice/group). Total RNA was extrancted and subjected to RNA-Seq.
2014-09-30 | E-GEOD-61875 | biostudies-arrayexpress
Project description:Double transgenic mice with hepatocyte-specific expression of AEG-1 and c-Myc show aggressive HCC compared to single transgenics. Gene expression was analyzed to understand the molecular mechanism by which AEG-1 and c-Myc cooperate to promote hepatocarcinogenesis.
2014-09-30 | GSE61875 | GEO
Project description:Whole exome sequencing and copy number analysis was performed on 231 hepatocellular carcinomas (72% with hepatitis B viral infection) that were classified as early-stage hepatocellular carcinomas, candidates for surgical resection. Recurrent mutations were validated by Sanger sequencing. Unsupervised genomic analyses identified an association between specific genetic aberrations and postoperative clinical outcomes. Recurrent somatic mutations were identified in 9 genes, including TP53, CTNNB1, AXIN1, RPS6KA3, and RB1. Recurrent homozygous deletions in FAM123A, RB1, and CDKN2A, and high-copy amplifications in MYC, RSPO2, CCND1, and FGF19 were detected. Pathway analyses of these genes revealed aberrations in the p53, Wnt, PIK3/Ras, cell cycle, and chromatin remodelling pathways. RB1 mutations were significantly associated with cancer-specific and recurrence-free survival after resection (p = 0.016 and p = 0.001, respectively). FGF19 amplifications, known to activate Wnt signalling, were mutually exclusive with CTNNB1 and AXIN1 mutations, and significantly associated with cirrhosis (p = 0.017). RB1 mutations can be used as a prognostic molecular biomarker for resectable hepatocellular carcinoma. Further study is required to investigate the potential role of FGF19 amplification in driving hepatocarcinogenesis in patients with liver cirrhosis and to investigate the potential of anti-FGF19 treatment in these patients.
2014-05-01 | GSE54504 | GEO
Project description:Fibroblast growth factor 19 (FGF19) is a gut-derived peptide hormone that is produced following activation of Farnesoid X Receptor (FXR). FGF19 is secreted and signals to the liver, where it contributes to the homeostasis of bile acid (BA), lipid and carbohydrate metabolism. FGF19 is a promising therapeutic target in metabolic syndrome and cholestatic diseases, but enthusiasm for its use has been tempered by FGF19-mediated induction of proliferation and hepatocellular carcinoma. To inform future rational design of FGF19-variants, we have conducted temporal quantitative proteomic and gene expression analyses to identify FGF19-targets related to metabolism and proliferation. Mice were fasted for 16 hours, and injected with human FGF19 (1 mg/kg body weight) or vehicle. Liver protein extracts (containing 'light' lysine) were mixed 1:1 with a spike-in protein extract from 13C6-lysine metabolically labelled mouse liver (containing 'heavy' lysine) and analysed by LC-MS/MS. Our analyses provide a resource of FGF19 target proteins in the liver. 189 proteins were upregulated (≥ 1.5 folds) and 73 proteins were downregulated (≤ -1.5 folds) by FGF19. FGF19 treatment decreased the expression of proteins involved in fatty acid (FA) synthesis, i.e. Fabp5, Scd1, and Acsl3 and increased the expression of Acox1, involved in FA oxidation. As expected, FGF19 increased the expression of proteins known to drive proliferation (i.e. Tgfbi, Vcam1, Anxa2 and Hdlbp). Importantly, many of the FGF19 targets (i.e. Pdk4, Apoa4, Fas and Stat3) have a dual function in both metabolism and cell proliferation. Therefore, our findings challenge the development of FGF19-variants that uncouple full metabolic benefit from mitogenic potential.
2017-02-15 | PXD005659 | Pride
Project description:Mouse FGF15 and human FGF19 are orthologous proteins that regulate bile acid metabolism. However, other hepatic functions of FGF15/19 are not well characterized. We used microarrays to analyze global hepatic gene expression in mice administered FGF15 or FGF19. Total liver RNA was isolated from wild-type mice administered vehicle, purified FGF15 or recombinant FGF19 for 6 hr via a jugular vein injection as described (Inagaki et al., 2005). Mice did not have access to food throughout the 6 hr treatment, and livers were harvested and immediately frozen in liquid nitrogen. Microarray analyses were performed using the Mouse Genome 430A 2.0 array.
2011-06-07 | E-GEOD-29426 | biostudies-arrayexpress
Project description:Cholesterol is an essential cell membrane component and precursor in metabolic pathways. Control of cholesterol levels is essential to human health. The endocrine hormone FGF19 potently inhibits CYP7A1, which controls a key step in cholesterol catabolism. However, the molecular mechanisms that integrate FGF19 with other cholesterol metabolic pathways are incompletely understood. Here we show that FGF19 and analogue promote HDL biogenesis and cholesterol efflux from the liver by selectively modulating liver X receptor signaling without inducing hepatic steatosis. We further identify ATP-binding cassette transporter A1 and FGFR4 as mediators of this effect. In dyslipidemic Apoe-/- mice fed a Western diet, treatment with FGF19 analogue dramatically reduced atherosclerotic lesion area in aortas. In healthy human volunteers, FGF19 analogue caused a placebo-adjusted increase in HDL cholesterol levels of 26% in seven days. These findings outline a regulatory role for FGF19 in cholesterol metabolism and advance our understanding of the mechanisms that coordinate sterol homeostasis. We used microarrays to detail the global programme of gene expression affected by FGF19 treatment in mice.
2019-01-25 | GSE117855 | GEO
Project description:Administration of FGF19 - a physiological regulator of bile acid homeostasis - to diabetic and diet-induced-obese mice can suppress plasma glucose concentration and improve insulin sensitivity. Repurposing FGF19 as a therapeutic agent for treating type 2 diabetes and cholestatic liver disease is therefore of significant interest. However, the tumorigenic risk associated with prolonged FGF19 administration is a major hurdle in realizing its full clinical potential. Here we show that non-mitogenic FGF19 variants that retain full beneficial glucose-lowering activity of wild-type FGF19 (FGF19WT) can be engineered by diminishing FGF19’s ability to induce dimerization of its cognate FGF receptors (FGFR). As proof-of-principle, we generated three such mutants, each with a partial defect in binding affinity to FGFR (FGF19ΔFGFR), and its co-receptors klotho (FGF19ΔKLB) or heparan sulfate (FGF19ΔHBS). Pharmacological assays in healthy and db/db mice confirmed that these variants incur a dramatic loss in mitogenic activity, yet are indistinguishable from FGF19WT in eliciting glycemic control. Our approach provides a simple framework for the development of safer and efficacious FGF19 analogs.
2020-12-07 | GSE148997 | GEO