Organoid models of fibrolamellar carcinoma mutations reveal hepatocyte transdifferentiation through cooperative BAP1 and PRKAR2A loss

Laura Rüland, Francesco Andreatta, Simone Massalini, Susana Chuva de Sousa Lopes, Hans Clevers, Delilah Hendriks, Benedetta Artegiani

Research output: Contribution to journal/periodicalArticleScientificpeer-review

6 Citations (Scopus)

Abstract

Fibrolamellar carcinoma (FLC) is a lethal primary liver cancer, affecting young patients in absence of chronic liver disease. Molecular understanding of FLC tumorigenesis is limited, partly due to the scarcity of experimental models. Here, we CRISPR-engineer human hepatocyte organoids to recreate different FLC backgrounds, including the predominant genetic alteration, the DNAJB1-PRKACA fusion, as well as a recently reported background of FLC-like tumors, encompassing inactivating mutations of BAP1 and PRKAR2A. Phenotypic characterizations and comparisons with primary FLC tumor samples revealed mutant organoid-tumor similarities. All FLC mutations caused hepatocyte dedifferentiation, yet only combined loss of BAP1 and PRKAR2A resulted in hepatocyte transdifferentiation into liver ductal/progenitor-like cells that could exclusively grow in a ductal cell environment. BAP1-mutant hepatocytes represent primed cells attempting to proliferate in this cAMP-stimulating environment, but require concomitant PRKAR2A loss to overcome cell cycle arrest. In all analyses, DNAJB1-PRKACAfus organoids presented with milder phenotypes, suggesting differences between FLC genetic backgrounds, or for example the need for additional mutations, interactions with niche cells, or a different cell-of-origin. These engineered human organoid models facilitate the study of FLC.

Original languageEnglish
Pages (from-to)2377
JournalNature Communications
Volume14
Issue number1
DOIs
Publication statusPublished - 03 May 2023

Keywords

  • Humans
  • Liver Neoplasms/metabolism
  • Cell Transdifferentiation/genetics
  • Carcinoma, Hepatocellular/metabolism
  • Mutation
  • Hepatocytes/metabolism
  • Organoids/metabolism
  • HSP40 Heat-Shock Proteins/metabolism
  • Tumor Suppressor Proteins/genetics
  • Ubiquitin Thiolesterase/genetics
  • Cyclic AMP-Dependent Protein Kinase RIIalpha Subunit/genetics

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