Expression of DNAJB1-PRKACA oncogene suppresses the differentiation potential of liver progenitor organoids towards a hepatocyte lineage
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, w...
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| Main Authors: | , , , , , , , , , , , , , |
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| Format: | Article |
| Language: | English |
| Published: |
Nature Portfolio
2025-07-01
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| Series: | Scientific Reports |
| Online Access: | https://doi.org/10.1038/s41598-025-11028-4 |
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| Summary: | 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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| ISSN: | 2045-2322 |