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<p>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 <i>DNAJB1-PRKACA</i> 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 <i>DNAJB1-PRKACA</i>. 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 <i>DNAJB1-PRKACA</i> 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 <i>DNAJB1-PRKACA</i>-expressing liver progenitor organoids displayed a markedly reduced capacity for hepatocyte differentiation. These findings suggest that the <i>DNAJB1-PRKACA</i> fusion gene disrupts the normal differentiation process of liver progenitor cells.</p>

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

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年7月16日

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  • 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,
  • Khashayar Vakili

摘要

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.