Timeframe: 2016 – 2018
Goal: Investigate DNAJB1-PRKACA fusion kinase function in new fibrolamellar carcinoma models
Principal Investigator: Dr. Yi Guo, PhD
Study overview: The DNAJB1-PRKACA fusion kinase is found in nearly 100% of FLC cases. While this novel fusion had previously been shown to promote tumors in mice, defining the mechanistic function of DNAJB1-PRKACA and the pathways it controls is critical for the development of targeted therapeutics. This project investigated the function of the DNAJB1-PRKACA fusion in FLC tumor formation using both Drosophila melanogaster (fruit fly) and mice models. The team had previously established a DNAJB1-PRKACA transgenic Drosophila model, in which the fusion is expressed in the eye where phenotypes are easily visible. This model demonstrates abnormal phenotypes affecting both proliferation and differentiation of Drosophila eyes. The study team also exploited CRISPR/Cas9 genome-engineering technology in murine cultured hepatocytes to recreate the endogenous chromosomal deletion found in FLC patients.
The goals of the study were to:
- Characterize the oncogenic and fibrogenic activities of genetic engineered murine hepatocytes in vitro and in vivo; and
- Screen potential therapeutics using the DNAJB1-PRKACA over-expression model in Drosophila, to provide essential resources and knowledge for future development of new FLC therapeutics.