Journal
PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA
Volume 114, Issue 50, Pages 13076-13084Publisher
NATL ACAD SCIENCES
DOI: 10.1073/pnas.1716483114
Keywords
fibrolamellar hepatocellular carcinoma; CRISPR; mouse cancer models; protein kinase A; beta-catenin
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Funding
- Starr Cancer Consortium [I10-0098]
- Marie-Josee and Henry R. Kravis Center for Molecular Oncology, National Cancer Institute Cancer Center Core Grants [P30-CA008748, NIH P01 CA013106]
- Andrew McDonough B+ Foundation
- National Center for Advancing Translational Sciences (NCATS) National Institutes of Health (NIH) Clinical and Translational Science Award (CTSA) program [UL1 TR001866]
- F31 NRSA predoctoral fellowship from the NCI/NIH [F31CA192835]
- NIH [1R56CA207929]
- MSKCC Single Cell Sequencing Initiative
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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 either 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 beta-catenin, an observation supported by evidence of recurrent Wnt pathway mutations in human FL-HCC, as well as treatment with the hepatotoxin 3,5-diethoxycarbonyl-1,4-dihydrocollidine, 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.
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