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Expression of DNAJB1-PRKACA oncogene suppresses the differentiation potential of liver progenitor organoids towards a hepatocyte lineage

Emma DiPietro,Nihal Bharath,Michael Karski,Olivia Durfee,Marc S. Sherman,Qianyi Ma,Liang Sun,Alaa R. Farghli,Colton J. Smith,Ina Kycia,Praveen Sethupathy,Wolfram Goessling,Michael S. Rogers,K. Vakili

Published 2025 in Scientific Reports

ABSTRACT

Fibrolamellar carcinoma (FLC) is a type of primary liver cancer that predominantly affects healthy adolescents and young adults in a background of normal liver. The DNAJB1-PRKACA fusion gene is an oncogenic driver in FLC tumors. To investigate the oncogenic mechanisms of this fusion gene, we developed a model using human liver progenitor organoids engineered to express DNAJB1-PRKACA. Single-nucleus RNA sequencing of these organoids revealed an upregulation of genes that significantly overlap with those expressed in FLC epithelial cells. Additionally, the expression of DNAJB1-PRKACA led to the downregulation of genes coding for markers of mature epithelial cells, indicating a shift toward a less differentiated state. When compared to wild-type liver progenitor organoids, which exhibit a strong ability to differentiate into hepatocytes, the DNAJB1-PRKACA-expressing liver progenitor organoids displayed a markedly reduced capacity for hepatocyte differentiation. These findings suggest that the DNAJB1-PRKACA fusion gene disrupts the normal differentiation process of liver progenitor cells.

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