CRISPR/Cas9 Engineering of Adult Mouse Liver Demonstrates That the Dnajb1-Prkaca Gene Fusion Is Sufficient to Induce...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• Fibrolamellar hepatocellular carcinoma (FL-HCC) is a rare liver cancer affecting young individuals.
• A specific gene fusion, DNAJB1-PRKACA, is frequently found in FL-HCC patients.
• The oncogenic role of the DNAJB1-PRKACA fusion in liver tumorigenesis remained unproven.

Purpose of the Study:

• To investigate if the DNAJB1-PRKACA gene fusion is sufficient to induce liver tumor formation.
• To create a mouse model for studying FL-HCC development and progression.

Main Methods:

• CRISPR/Cas9 gene editing was used to create the DNAJB1-PRKACA fusion in wild-type mice.
• Vectors were delivered to mouse livers via hydrodynamic tail vein injection.
• Tumor development was monitored for 14 months, with comprehensive genomic and histologic analysis.

Main Results:

• Mice engineered to have the DNAJB1-PRKACA fusion developed liver neoplasms.
• The induced tumors exhibited histologic and cytologic features characteristic of human FL-HCC.
• Genomic analysis revealed significant alterations in cell cycle and mitosis genes, similar to human FL-HCC, and a lack of common liver cancer mutations.

Conclusions:

• The DNAJB1-PRKACA fusion gene is sufficient to initiate the formation of FL-HCC-like tumors in mice.
• This study provides a novel mouse model for FL-HCC research.
• Targeting the DNAJB1-PRKACA fusion presents a potential therapeutic strategy for FL-HCC.