DNAJB1–PRKACA fusion kinase interacts with β-catenin and the liver regenerative response to drive fibrolamellar hepatocellular carcinoma
| Autor: | Timour Baslan, Darjus F. Tschaharganeh, Shauna L. Houlihan, Gadi Lalazar, Edward R. Kastenhuber, Chi-Chao Chen, Sanford M. Simon, Sha Tian, Benedikt Bosbach, David Requena, Scott W. Lowe, John E. Wilkinson |
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| Rok vydání: | 2017 |
| Předmět: |
0301 basic medicine
0303 health sciences Multidisciplinary Wild type Wnt signaling pathway Biological Sciences Biology medicine.disease_cause medicine.disease Fusion protein 3. Good health PRKACA Fusion gene 03 medical and health sciences 0302 clinical medicine 030104 developmental biology Fibrolamellar hepatocellular carcinoma 030220 oncology & carcinogenesis Catenin Cancer research medicine Carcinogenesis Liver cancer 030304 developmental biology |
| Zdroj: | Proceedings of the National Academy of Sciences. 114:13076-13084 |
| ISSN: | 1091-6490 0027-8424 |
| DOI: | 10.1073/pnas.1716483114 |
| Popis: | A segmental deletion resulting in DNAJB1-PRKACA gene fusion is now recognized as the signature genetic event of fibrolamellar hepatocellular carcinoma (FL-HCC), a rare but lethal liver cancer that primarily affects adolescents and young adults. Here, we implement CRISPR/Cas9 genome editing and transposon-mediated somatic gene transfer to demonstrate that expression of both the endogenous fusion protein or a chimeric cDNA leads to the formation of indolent liver tumors in mice that closely resemble human FL-HCC. Notably, overexpression of the wild type PRKACA was unable to fully recapitulate the oncogenic activity of DNAJB1-PRKACA, implying that FL-HCC does not simply result from enhanced PRKACA expression. Tumorigenesis was significantly enhanced by genetic activation of β-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine (DDC), which causes tissue injury, inflammation and fibrosis. Our study validates the DNAJB1-PRKACA fusion kinase as an oncogenic driver and candidate drug target for FL-HCC and establishes a practical model for preclinical studies to identify strategies to treat this disease.SignificanceEfforts to understand and treat FL-HCC have been confounded by a lack of models that accurately reflect the genetics and biology of the disease. Here, we demonstrate that the Dnajb1-Prkaca gene fusion drives tumorigenesis in mice, and that fusion to DNAJB1 drives FL-HCC initiation more effectively than wild type PRKACA overexpression. The requirement of the PRKACA kinase domain in tumor initiation establishes the potential utility of kinase inhibitors targeting the fusion. By identifying genetic and environmental factors that can enhance the consistency and aggressiveness of disease progression, we reveal biological characteristics of the disease and advance a robust platform for future pre-clinical studies. |
| Databáze: | OpenAIRE |
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