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PreprintCited by 11Fibroblast Growth Factor ResearchHepatocellular Carcinoma Treatment and PrognosisLiver physiology and pathology

The DOI matches its Crossref record; 1 of the 1 references it cites were found in a registry or an index.

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

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Ursic-Bedoya, José, Desandré, Guillaume, Chavey, Carine, Marie, Pauline, Polizzi, Arnaud, Rivière, Benjamin, Guillou, Hervé, Assenat, Eric, Hibner, Urszula, Gregoire, Damien·2023·EMBO Molecular Medicine
DOI 10.1101/2023.09.15.557921PMC PMC10897482

Preprint — published as 10.1038/s44321-023-00021-x · Paper page

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Abstract

FGF19 hormone has pleiotropic metabolic functions, notably 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.

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Metadata

Authors
Ursic-Bedoya, J., Desandré, G., Chavey, C., Marie, P., Polizzi, A., Rivière, B., Guillou, H., Assenat, E., Hibner, U., & Gregoire, D.
Affiliations
  • Centre National de la Recherche Scientifique (FR)
  • Université Toulouse III - Paul Sabatier (FR)
  • Université de Montpellier (FR)
Corresponding author
Desandré, Guillaume
ORCID
Venue
EMBO Molecular Medicine
Publisher
openRxiv
Published
2023-09-17
Volume
16
Issue
2
Pages
238-250
ISSN
1757-4676 (ISSN-L)
DOI
10.1101/2023.09.15.557921
PMC
PMC10897482
OpenAlex
W4390904460
Cited by
11
References
1
Citations by year
2026: 5 · 2025: 3 · 2024: 3
FWCI
1.49
Type
journal article
Language
en
Open access
Licence
cc-by
Locations
  • EMBO Molecular Medicine (publishedVersion, cc-by)
  • bioRxiv (Cold Spring Harbor Laboratory) (acceptedVersion, cc-by-nc-nd)
  • PubMed Central (publishedVersion, cc-by)
  • PubMed (publishedVersion)
  • HAL (submittedVersion, cc-by-nc-nd)
  • HAL (submittedVersion, cc-by-nc-sa)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
Funders
  • Institut National de la Santé et de la Recherche Médicale
  • Fondation ARC pour la Recherche sur le Cancer
  • Institut National Du Cancer (INCa_Inserm_DGOS_12553, 2019-134)
  • Association Française pour l'Etude du Foie (AAP_2021)
  • Direction Générale de l’offre de Soins
Topics
  • Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Fibroblast Growth Factor Research
  • Health Sciences › Medicine › Hepatology › Hepatocellular Carcinoma Treatment and Prognosis
  • Health Sciences › Medicine › Hepatology › Liver physiology and pathology
Keywords
FGF19, c-Myc, hepatocellular carcinoma, hepatocarcinogenesis, oncogene cooperation, p53 inactivation, CTNNB1 mutation, hepatocyte proliferation, drug safety concerns
MeSH terms
Animals, Fibroblast Growth Factors, Carcinoma, Hepatocellular, Hormones, Humans, Liver Neoplasms, Mice

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