2. Academic Validation
  3. Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids

Cholangiocarcinoma progression depends on the uptake and metabolization of extracellular lipids

  • Hepatology. 2022 Jan 14. doi: 10.1002/hep.32344.
Mikel Ruiz de Gauna 1,  Francesca Biancaniello 2 3,  Francisco González-Romero 1,  Pedro M Rodrigues 2 4 5,  Ainhoa Lapitz 2,  Beatriz Gómez-Santos 1,  Paula Olaizola 2,  Sabina Di Matteo 2 3,  Igor Aurrekoetxea 1 6,  Ibone Labiano 2,  Ane Nieva-Zuluaga 1,  Asier Benito-Vicente 7 8,  María J Perugorria 2 4,  Maider Apodaka-Biguri 1,  Nuno A Paiva 2,  Diego Sáenz de Urturi 1,  Xabier Buqué 1,  Igotz Delgado 1,  César Martín 7 8,  Mikel Azkargorta 9,  Felix Elortza 4 9,  Diego F Calvisi 10,  Jesper B Andersen 11,  Domenico Alvaro 3,  Vincenzo Cardinale 12,  Luis Bujanda 2 4,  Jesús M Banales 2 4 5 13,  Patricia Aspichueta 1 4 6
Affiliations

Affiliations

  • 1 Faculty of Medicine and Nursing, Department of Physiology, University of the Basque Country (UPV/EHU), Leioa, Spain.
  • 2 Department of Liver and Gastrointestinal Diseases, Biodonostia Health Research Institute, Donostia University Hospital, University of the Basque Country (UPV/EHU), San Sebastian, Spain.
  • 3 Department of Translational and Precision Medicine, "Sapienza" University of Rome, Rome, Italy.
  • 4 National Institute for the Study of Liver and Gastrointestinal Diseases (CIBERehd, Carlos III Health Institute), Madrid, Spain.
  • 5 IKERBASQUE, Basque Foundation for Science, Bilbao, Spain.
  • 6 Biocruces Bizkaia Health Research Institute, Cruces University Hospital, Barakaldo, Spain.
  • 7 Department of Molecular Biophysics, Biofisika Institute (University of Basque Country and Consejo Superior de Investigaciones Científicas (UPV/EHU, CSIC), Leioa, Spain.
  • 8 Department of Biochemistry and Molecular Biology, University of the Basque Country (UPV/EHU), Leioa, Spain.
  • 9 Proteomics Platform, CIC bioGUNE, BRTA (Basque Research and Technology Alliance), ProteoRed-ISCIII, CIBERehd, Bizkaia Science and Technology Park, Derio, Spain.
  • 10 Institute of Pathology, University of Regensburg, Regensburg, Germany.
  • 11 Biotech Research & Innovation Centre (BRIC), Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark.
  • 12 Department of Medico-Surgical Sciences and Biotechnology, "Sapienza" University of Rome, Rome, Italy.
  • 13 Department of Biochemistry and Genetics, School of Sciences, University of Navarra, Pamplona, Spain.
PMID: 35030285 DOI: 10.1002/hep.32344
Abstract

Background and aims: Cholangiocarcinoma (CCA) includes a heterogeneous group of biliary cancers with a dismal prognosis. We investigated if lipid metabolism is disrupted in CCA and its role in tumor proliferation.

Approach and results: The in vitro and in vivo tumorigenic capacity of five human CCA cell lines was analyzed. Proteome, lipid content, and metabolic fluxes were evaluated in CCA cells and compared with normal human cholangiocytes (NHC). The Akt1/NOTCH1 intracellular cytoplasmic domain (Nicd1)-driven CCA mouse model was also evaluated. The proteome of CCA cells was enriched in pathways involved in lipid and lipoprotein metabolism. The EGI1 CCA cell line presented the highest tumorigenic capacity. Metabolic studies in high (EGI1) versus low (HUCCT1) proliferative CCA cells in vitro showed that both EGI1 and HUCCT1 incorporated more fatty acids (FA) than NHC, leading to increased triglyceride storage, also observed in Akt1/Nicd1-driven CCA mouse model. The highly proliferative EGI1 CCA cells showed greater uptake of very-low-density and HDLs than NHC and HUCCT1 CCA cells and increased cholesteryl ester content. The FA oxidation (FAO) and related proteome enrichment were specifically up-regulated in EGI1, and consequently, pharmacological blockade of FAO induced more pronounced inhibition of their tumorigenic capacity compared with HUCCT1. The expression of acyl-CoA dehydrogenase ACADM, the first Enzyme involved in FAO, was increased in human CCA tissues and correlated with the proliferation marker PCNA.

Conclusions: Highly proliferative human CCA cells rely on lipid and lipoprotein uptake to fuel FA catabolism, suggesting that inhibition of FAO and/or lipid uptake could represent a therapeutic strategy for this CCA subclass.

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