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 () and Benedetta Artegiani ()
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Laura Rüland: The Princess Maxima Center for Pediatric Oncology
Francesco Andreatta: The Princess Maxima Center for Pediatric Oncology
Simone Massalini: The Princess Maxima Center for Pediatric Oncology
Susana Chuva de Sousa Lopes: Leiden University Medical Center
Hans Clevers: The Princess Maxima Center for Pediatric Oncology
Delilah Hendriks: Royal Netherlands Academy of Arts and Sciences
Benedetta Artegiani: The Princess Maxima Center for Pediatric Oncology

Nature Communications, 2023, vol. 14, issue 1, 1-20

Abstract: 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.

Date: 2023
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DOI: 10.1038/s41467-023-37951-6

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