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β-catenin-activated hepatocellular carcinomas are addicted to fatty acids
  1. Nadia Senni1,2,3,4,
  2. Mathilde Savall1,2,3,4,
  3. David Cabrerizo Granados1,2,3,4,
  4. Marie-Clotilde Alves-Guerra1,2,3,4,
  5. Chiara Sartor1,2,3,4,
  6. Isabelle Lagoutte1,2,3,
  7. Angélique Gougelet1,2,3,4,
  8. Benoit Terris1,2,3,4,5,
  9. Hélène Gilgenkrantz1,2,3,4,
  10. Christine Perret1,2,3,4,
  11. Sabine Colnot1,2,3,4,
  12. Pascale Bossard1,2,3,4
  1. 1 INSERM, U1016, Institut Cochin, Paris, France
  2. 2 CNRS, UMR8104, Paris, France
  3. 3 Université Paris Descartes, Sorbonne Paris Cité, Paris, France
  4. 4 Equipe Labellisée Ligne Nationale Contre le Cancer, Paris, France
  5. 5 Pathology Department, APHP, Hôpitaux Universitaires Paris Centre, Hôpital Cochin, Paris, France
  1. Correspondence to Dr Pascale Bossard, Inserm U1016, Institut Cochin, CNRS UMR8104, Université Paris Descartes, Paris75014, France; pascale.bossard{at}


Objectives CTNNB1-mutated hepatocellular carcinomas (HCCs) constitute a major part of human HCC and are largely inaccessible to target therapy. Yet, little is known about the metabolic reprogramming induced by β-catenin oncogenic activation in the liver. We aimed to decipher such reprogramming and assess whether it may represent a new avenue for targeted therapy of CTNNB1-mutated HCC.

Design We used mice with hepatocyte-specific oncogenic activation of β-catenin to evaluate metabolic reprogramming using metabolic fluxes on tumourous explants and primary hepatocytes. We assess the role of Pparα in knock-out mice and analysed the consequences of fatty acid oxidation (FAO) using etomoxir. We explored the expression of the FAO pathway in an annotated human HCC dataset.

Results β-catenin-activated HCC were not glycolytic but intensively oxidised fatty acids. We found that Pparα is a β-catenin target involved in FAO metabolic reprograming. Deletion of Pparα was sufficient to block the initiation and progression of β-catenin-dependent HCC development. FAO was also enriched in human CTNNB1-mutated HCC, under the control of the transcription factor PPARα.

Conclusions FAO induced by β-catenin oncogenic activation in the liver is the driving force of the β-catenin-induced HCC. Inhibiting FAO by genetic and pharmacological approaches blocks HCC development, showing that inhibition of FAO is a suitable therapeutic approach for CTNNB1-mutated HCC.

  • liver metabolism
  • hepatocellular carcinoma
  • lipid oxidation
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  • CP and SC contributed equally.

  • Contributors PB: conceived and supervised the study, analysed the data, carried out the experiments, wrote the manuscript and funding. NS: designed and carried out experiments and analysed the data. MS, DCG and CS: performed experiments. AG: technical advises and reading of the manuscript. IL: acquisition of ultrasound data. HG: axin1 animal model and critical reading of the manuscript. BT: provided the human samples. CP: funding, heatmap generation and analysis, critical revision of the data and critical reading of the manuscript. SC: funding, GSEA analysis and critical reading of the manuscript.

  • Funding NS is a recipient of Ligue Nationale Contre le Cancer (LNCC) and ARC foundation scholarships. MS is a recipient of the French Ministry of Research scholarship. This study was supported by grants from the ANR (Agence Nationale de la Recherche), the AFEF (Association Française d’Hépatologie) and the LNCC.

  • Competing interests None declared.

  • Patient consent Not required.

  • Provenance and peer review Not commissioned; externally peer reviewed.

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